Aetiology

HTG may be genetic (primary) or acquired (secondary). Genetic causes may be monogenic or polygenic, but a monogenic cause is relatively rare.[5][13]

Primary/genetic causes include monogenic chylomicronaemia (formerly known as hyperlipoproteinaemia [HLP] type 1 or familial chylomicronaemia syndrome), multifactorial or polygenic chylomicronaemia (formerly HLP type 5 or mixed hyperlipidaemia), multifactorial or polygenic HTG (formerly HLP type 4 or familial HTG), dysbetalipoproteinaemia (formerly HLP type 3 or dysbetalipoproteinaemia), and combined hyperlipoproteinaemia (formerly HLP type 2B or familial combined hyperlipidaemia).[5][12]

Secondary factors may contribute to clinical expression of HTG, but this often occurs on a background of polygenic susceptibility. Secondary causes of HTG include medical conditions, lifestyle factors, and drugs:[4][5][9]​ 

  • Medical conditions: diabetes mellitus, metabolic syndrome, insulin resistance, obesity, chronic kidney disease, nephrotic syndrome, hypothyroidism, pregnancy (particularly in the third trimester when triglyceride elevation associated with pregnancy is peaking), myeloma, systemic lupus erythematosus, liver disease, HIV infection, Cushing syndrome, sarcoidosis

  • Lifestyle factors: excessive alcohol consumption; diet high in saturated fat, sugar, or high glycaemic index foods; sedentary lifestyle

  • Drugs: glucocorticoids, anabolic steroids, oral oestrogens, thiazide and loop diuretics, non-cardioselective beta-blockers, isotretinoin, bexarotene, propofol, bile acid sequestrants, cyclophosphamide, asparaginase, capecitabine, interferon, tacrolimus, sirolimus, ciclosporin, protease inhibitors, second-generation antipsychotic agents (e.g., clozapine, olanzapine).

Pathophysiology

Triglycerides (TG) are transported in the body in TG-rich lipoproteins that are composed of core lipids (TG and cholesterol esters) and surface apolipoproteins, phospholipids, and free cholesterol; the two main types of TG-rich lipoproteins are chylomicrons and very low-density lipoproteins (VLDL).[5][13] Chylomicrons are secreted by the intestine and transport exogenous (dietary) TG, while VLDL is secreted by the liver and transports TG of endogenous origin.[13][19] VLDL particles are delivered to peripheral tissues where they are metabolised by endothelial-bound lipoprotein lipase (LPL) for energy utilisation (muscle tissue) or storage (adipose tissue).[19] Both chylomicron and VLDL particles are cleared by a common pathway that centres on LPL, which leaves remnant particles for catabolism.[19] Both chylomicron and VLDL remnants are taken up by the liver, though some VLDL remnants undergo further hydrolysis by hepatic lipase, which leads to generation of low-density lipoprotein (LDL) particles.[13] The level of TG circulating is determined by the efficiency of both LPL-mediated lipolysis and subsequent uptake of remnant particles, which are saturable mechanisms, and as secretion rates and plasma TG levels rise, lipolysis falls.[19][20][21]

When LPL activity is decreased for either genetic or acquired reasons, clearance of TG-rich lipoprotein particles of both exogenous and endogenous origin is impaired, resulting in their accumulation in the blood.[5][19] Extrinsic factors such as overweight or obesity, consuming a diet high in saturated fat or high glycaemic index foods, and ethanol consumption can lead to HTG by increasing chylomicron and VLDL production. Interventions that lower TG levels can both reduce VLDL production and promote VLDL clearance, or both.[5][19]

Other lipoprotein disturbances associated with HTG include an increase in non-high-density lipoprotein (non-HDL) cholesterol levels, because VLDL and remnants are important components of the non-HDL family of lipoproteins.[22][23][24][25]​​​ Also, apolipoprotein B (apoB) levels are typically increased, because full-length apoB-100 is a key structural component of both VLDL and its remnants.[23] The levels of remnant cholesterol are elevated in HTG, and it appears that the cholesterol content of remnant particles is much more proactively atherogenic than the TG content.[22] Also, patients with HTG have increased levels of qualitatively deleterious and highly atherogenic small, dense LDL particles.[22][23]​​​ Finally, HDL particles are almost always decreased in patients with HTG; decreased activities of cholesterol ester transfer protein (CETP) and LPL result in decreased production and altered HDL composition, which increases HDL catabolism.[19][26]​​​ The principal clinical consequence of mild-to-moderate HTG is the incremental or residual risk of the end points of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction and stroke, after accounting for levels of atherogenic LDL cholesterol.[27]​ In contrast, the main clinical concern of severe HTG is the heightened risk of acute pancreatitis, especially in children and young adults with monogenic familial chylomicronaemia syndrome due to severe genetic impairment of plasma lipolysis.[28]​ In adults with severe HTG due to multifactorial chylomicronaemia, there is additional risk of ASCVD endpoints on top of increased risk of acute pancreatitis.[28]​

Classification

HTG can be classified two ways: 1) according to the severity of the triglyceride (TG) elevation; and 2) whether the TG elevation is primary (genetic) or secondary (acquired).[5][6]

Historical classifications for HTG phenotypes were based on qualitative and quantitative biochemical differences in plasma lipoproteins (e.g., the Fredrickson or World Health Organization International Classification of Diseases [ICD] hyperlipoproteinaemia [HLP] phenotypes).[7] However, most laboratories no longer have the technology or know-how to perform this complex phenotyping. Furthermore, no randomised controlled evidence exists to show that clinical outcomes are altered through use of this system. Therefore, a streamlined classification system based simply on the TG level is currently preferred.[5]

Different guidelines and societies have different values for classification of severity of HTG.

  • Endocrine Society:[8]

    • Normal TG: <1.7 mmol/L (<150 mg/dL)

    • Mild HTG: 1.7 to 2.3 mmol/L (150-199 mg/dL)

    • Moderate HTG: 2.3 to 11.2 mmol/L (200-999 mg/dL)

    • Severe HTG: 11.2 to 22.4 mmol/L (1000-1999 mg/dL)

    • Very severe HTG: >22.4 mmol/L (≥2000 mg/dL)

  • American Heart Association/American College of Cardiology:[2]

    • Moderate HTG: 2.0 to 5.6 mmol/L (175-499 mg/dL)

    • Severe HTG: ≥5.6 mmol/L (≥500 mg/dL)

      Note: for moderate HTG, the 2021 American College of Cardiology expert consensus uses a definition of fasting TG ≥1.7 mmol/L (≥150 mg/dL) or non-fasting TG ≥2.0 mmol/L (≥175 mg/dL) and TG <5.6 mmol/L (<500 mg/dL).[9]

  • Adult Treatment Panel (ATP) III guidelines of the National Cholesterol Education Program:[10]

    • Normal fasting TG: <1.7 mmol/L (<150 mg/dL)

    • Borderline elevated TG: 1.7 to 2.3 mmol/L (150-199 mg/dL)

    • High TG: 2.3 to 5.6 mmol/L (200-499 mg/dL)

    • Very high TG: >5.6 mmol/L (≥500 mg/dL)

  • European Society of Cardiology/European Atherosclerosis Society:[11]

    • Mild-to-moderate HTG: 2-10 mmol/L (175-885 mg/dL)

    • Severe HTG: >10 mmol/L (>885 mg/dL)

The fact that various classification schemes exist indicates that no single scheme is the most useful or predominant in the clinic.

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