At a Glance

This rare autosomal recessive disorder (frequency 1 per million) is characterized by the absence of lipoprotein lipase (LPL) activity. A founder effect renders the frequency of this disease much higher in certain populations, such as French-Canadians (1:5000). LPL is a key enzyme involved with the hydrolysis of triglycerides (TG) in plasma to free fatty acids, which are then removed from the plasma to be used for energy in muscle or storage in adipose tissue. The milky, lipemic plasma seen in LPL deficiency (even under fasting conditions) is due to the accumulation of dietary fat in plasma as TG-rich chylomicrons. Males and females are equally affected.

Familial LPL deficiency should be considered in anybody with the chylomicronemia syndrome (massive plasma elevations of the large lipoprotein particles that originate from dietary fat, with a concomitant increase in TG concentrations), especially in the absence of secondary causes of hypertriglyceridemia.

This disorder usually presents in childhood following repeated episodes of abdominal pain (including colicky infants), sometimes radiating to the back, attacks of pancreatitis and eruptive cutaneous xanthomas in about 50% of patients (when TG levels exceed 22.5 mmol/L or 2000 mg/dL). These non-tender yellow papular lesions are located in areas of injury or pressure (e.g. the buttocks, knees, elbows and back). They result from foam cell deposition within the skin and are more common in adult patients than children.

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Hepatomegaly is common, and, if the plasma TG levels are very high, splenomegaly may also be seen. Organomegaly occurs as a result of TG uptake by macrophages, which become foam cells and may rapidly regress with a decrease in dietary fat intake. Lipemia retinalis, detectable by fundoscopy, develops when TG levels exceed 45 mmol/L (4000 mg/dL), although vision is unaffected. Severity of symptoms depends on degree of chylomicronemia, in turn related to dietary fat intake. Young patients learn to prevent the pain by avoiding fatty foods.

Other presenting symptoms may include diarrhea, internal bleeding and dyspnea. LPL deficiency is unlikely to be associated with atherosclerosis but recurrent pancreatitis may be life-threatening. Infant patients display failure to thrive, whereas elderly patients may have memory deficits and sensory neuropathy.

More severe hypertriglyceridemia can occur in compound heterozygotes, when other known genetic defects are present in addition to the heterozygous LPL state (e.g., the apoE2 allele, familial combined hyperlipidemia (FCH) and hepatic lipase deficiency). LPL promoter mutations are not rare and may contribute to the lipoprotein phenotype of FCH, at least in the subset of patients who show reduced postheparin plasma LPL activity.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A presumptive diagnosis can be made if a marked decrease in plasma TG occurs after 1 week on a severely restricted low-fat diet. In this instance, apoC-II deficiency must also be considered.

Clinical diagnosis of LPL deficiency requires the specific assay of LPL activity in plasma after heparin administration, when marked reduction or absence of LPL activity is observed.

The definitive diagnosis of LPL deficiency is often confirmed by genetic analysis in probands and family members of structural defects in the LPL gene.

Test Results Indicative of the Disorder

LPL deficiency is characterized biochemically by elevated TG (often >11.3 mmol/L or 1000 mg/dL) and lowered high-density lipoprotein cholesterol (HDL-C; often <0.5 mmol/L) in plasma. VLDL levels may remain fairly normal.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Secondary causes of hypertriglyceridemia include diabetes, alcohol intake, hypothyroidism, renal failure, glucocorticoid, or any of several pharmaceutical agents (e.g., sertraline, beta-blockers, certain hypertensive agents, estrogen therapy, and HIV protease inhibitors).

What Lab Results Are Absolutely Confirmatory?

Close to 100 mutations in the LPL gene have been associated with LPL deficiency. Definitive diagnosis of LPL deficiency requires either a postheparin plasma LPL assay or DNA analysis of the LPL gene. DNA sequence analysis is becoming the most readily applied method of diagnosis. Heterozygotes show a 50% decrease in LPL in postheparin plasma but have normal or only slightly abnormal plasma lipid levels.

LPL deficiency is distinguished from the phenotypically similar apoC-II deficiency, by restoration of normal LPL activity on addition of functional apoC-II to the postheparin plasma LPL assay of by the presence of homozygous mutations in the APOC2 gene rather than the LPL gene.

Mixed hyperlipidemia also causes chylomicronemia and affects about 1 in 600 individuals. However, it is most typically associated with elevated VLDL-C levels, whereas chylomicrons are often the primary source of triglyceride elevations in LPL deficiency.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Mild hyperlipidemia, mainly an increase in TG and a decrease in HDL-C, may be observed in the parents and relatives of some patients with LPL deficiency, whereas families of other probands are normolipidemic.