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Key Points

  • Disease summary:

    • Common hypertriglyceridemia can be considered a polygenic disorder, involving the interaction of often multiple genetic loci, many yet to be identified, and environmental factors.

    • Hypertriglyceridemia can be divided into primary versus secondary causes.

    • Although clinical manifestations of hypertriglyceridemia are often rare, those with primary hypertriglyceridemia may have eruptive xanthoma, tuberous xanthoma, palmar xanthoma, or lipemia retinalis.

    • Both primary and secondary hypertriglyceridemia can present with pancreatitis, particularly if triglyceride (TG) levels exceed 1000 mg/dL.

  • Differential diagnosis:

    • For primary hypertriglyceridemia, the differential includes lipoprotein lipase (LPL) deficiency, apolipoprotein (Apo) C-II, familial hypertriglyceridemia, familial combined hyperlipidemia while the most common secondary causes of hypertriglyceridemia are obesity, excess alcohol consumption, diabetes (poorly controlled), hypothyroidism, and medications such as thiazides, antipsychotic medications, antiretroviral medications.

  • Monogenic forms:

    • A few individuals with plasma TG levels greater than 95th percentile have rare monogenic disorders resulting from homozygous loss-of-function mutations, including in the LPL and Apo genes APOC2 and APOA5.

  • Family history:

    • A family history of severe hypertriglyceridemia, recurrent pancreatitis in affected members, or of cutaneous manifestations increase the likelihood of primary hypertriglyceridemia.

  • Environmental factors:

    • Several environmental factors such as obesity, diabetes, hypothyroidism, pregnancy, alcohol intake, and certain medications can exacerbate hypertriglyceridemia in those with a genetic predisposition to hypertriglyceridemia.

  • Genome-wide association studies:

    • For children with suspected LPL deficiency, sequencing of candidate genes is now the most expeditious method to make a diagnosis. Genome-wide association studies (GWAS) have shown that for common hypertriglyceridemia, common small-to-moderate effect variants and rare large-effect mutations are both determinant of triglyceride levels, but there is no allelic risk score yet established. Thus, genetic screening for common, less severe hypertriglyceridemia in adults is not presently recommended.

  • Pharmacogenomics:

    • There is no evidence yet that genotypes for common single-nucleotide polymorphism (SNP) variants from GWAS determine pharmacogenetic response of hypertriglyceridemia to interventions.

Diagnostic Criteria for Hypertriglyceridemia

According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the severity of hypertriglyceridemia can be classified as follows:

Clinical Characteristics

Although most patients with hypertriglyceridemia have no clinical manifestations, those with primary causes of hypertriglyceridemia (see later) or severe elevations in plasma TG levels may have characteristic clinical findings. Several variations of xanthoma may be evident in primary hypertriglyceridemia. Eruptive xanthomas are small (2-5 mm in diameter) raised yellow lesions that occur most typically on the trunk, buttocks, or extremities while tuberous xanthomas are larger (<3 cm in diameter), reddish or orange, shiny, nontender, mobile nodules present on extensor surfaces. The former is most often encountered where there is marked elevation in chylomicrons, such as in familial hyperchylomicronemia (type I hyperlipidemia) or mixed (type V) hyperlipidemia, while the latter is often seen in type III hyperlipidemia (or familial dysbetalipoproteinemia). The presence of yellowish deposits within palmar creases (palmar xanthomas) is pathognomonic for type III hyperlipidemia. Individuals with types I or V hyperlipidemia may also exhibit hepatosplenomegaly, recurrent epigastric pain with predisposition to pancreatitis, focal neurologic symptoms such as irritability, as well as lipemia retinalis. Lipemia retinalis refers to a milky appearance of the retinal vessels, often when TG levels exceed 3100 mg/dL (~35 mmol/L). Pancreatitis can occur in individuals with primary or secondary hypertriglyceridemia, and the risk for pancreatitis is greatly increased once TG levels are greater than 1000 mg/dL (>11.3 mmol/L).

Differential Diagnosis

Hypertriglyceridemia can be classified into primary and secondary causes (Table 14-1).


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