A. Chait, R. Eckel
Apr 30, 2019
Citations
5
Influential Citations
67
Citations
Journal
Annals of Internal Medicine
Abstract
Key Summary Points The chylomicronemia syndrome describes a constellation of findings that occur with extreme elevations in plasma triglyceride levels. The syndrome has 3 major causes: multifactorial chylomicronemia syndrome (MFCS), familial chylomicronemia syndrome (FCS), and familial partial lipodystrophy (FPLD). MFCS is by far the most common cause of the chylomicronemia syndrome and usually results from the coexistence of genetic forms of hypertriglyceridemia with 1 or more secondary causes of hypertriglyceridemia. FCS and FPLD are rare. The major goals of treatment are to lower triglyceride levels sufficiently to prevent acute pancreatitis and then to prevent atherosclerotic cardiovascular disease. Therapeutic approaches to the 3 major causes of the chylomicronemia syndrome (MFCS, FCS, and FPLD) differ considerably. The term chylomicronemia syndrome first appeared in the scientific literature in 1981 to describe clinical features attributed to marked elevations in plasma triglyceride levels in a small number of patients (1). Features included abdominal pain, acute pancreatitis, eruptive xanthomas, lipemia retinalis, mental confusion, memory loss, and flushing with minimal alcohol intake (1). Several of these characteristics resembled those seen in Fredrickson type 1 hyperlipoproteinemia, a condition resulting from deficient lipoprotein lipase (LPL) activity (2). Because most patients in our original series had type 2 diabetes concurrent with a familial form of hypertriglyceridemia rather than primary LPL deficiency as a cause of their marked hypertriglyceridemia, we attributed the symptoms to the severe hypertriglyceridemia itself (1). This assumption was supported further by the observation that abdominal pain, mental confusion, and memory loss improved with lipid-lowering therapy. Clinical features, including abdominal pain and acute pancreatitis, eruptive xanthomas, and lipemia retinalis, occur regardless of the cause of severe hypertriglyceridemia. The most serious consequences of the chylomicronemia syndrome are acute pancreatitis, which often is recurrent, and, subsequently, atherosclerotic cardiovascular disease (CVD), depending on the cause of the chylomicronemia syndrome. Over the years, chylomicronemia syndrome often has been used synonymously with familial chylomicronemia syndrome (FCS), which results from mutations in LPL and several related genes (see later). However, the diagnosis and management of chylomicronemia syndrome from causes other than FCS frequently are misunderstood. In this review, we discuss the physiology of triglyceride clearance from plasma; the 3 major groups of conditions that lead to the chylomicronemia syndrome, as well as their relative frequencies; the consequences of chylomicronemia syndrome, with an emphasis on acute pancreatitis; and an approach to therapy. Methods This update used PubMed Central. Search terms included chylomicronemia; chylomicronemia syndrome; chylomicronemia treatment; chylomicronemia genetics; severe hypertriglyceridemia; severe hypertriglyceridemia, acquired; severe hypertriglyceridemia drugs; severe hypertriglyceridemia treatment; type 1 hyperlipoproteinemia; lipoprotein lipase deficiency; familial chylomicronemia syndrome; familial partial lipodystrophy; Dunnigan lipodystrophy; Kbberling lipodystrophy; acute pancreatitis; glycosylphosphatidylinositol-anchored high-density lipoproteinbinding protein 1; apolipoprotein CII; apolipoprotein CIII; alipogene tiparvovec; lipase maturation factor 1; angiopoietin 3; angiopoietin 4; angiopoietin 8; apolipoprotein CIII antisense oligonucleotide, and angiopoietin 3 inhibitors. Physiology of the Catabolism of Triglyceride-Rich Lipoproteins Triglycerides in both chylomicrons, which transport dietary fat, and very-low-density lipoprotein (VLDL), which transports endogenous triglycerides formed by the liver, are hydrolyzed by LPL, which is the major mechanism for clearance of the triglyceride-rich lipoproteins. Lipoprotein lipase is synthesized by several tissues, including adipose tissue and skeletal and cardiac muscle, then transported by glycosylphosphatidylinositol-anchored high-density lipoproteinbinding protein 1 (GPIHBP1) to the luminal side of the endothelium, where it binds glycosaminoglycans and is available to hydrolyze triglycerides (3). Several other proteins regulate LPL activity (4): Apolipoprotein (apo) CII and apo CIII activate and inhibit LPL, respectively; apo E plays an important role in uptake and clearance of the remnants of the triglyceride-rich lipoproteins; and lipase maturation factor 1 (LMF1) plays a role in lipase maturation (5, 6). Because inhibition of apo CIII with an antisense oligonucleotide has lowered plasma triglyceride levels in persons with nonfunctioning LPL (7), apo CIII seems to inhibit the turnover of triglyceride-rich lipoproteins, primarily through a hepatic clearance mechanism involving the axis of low-density lipoprotein (LDL) receptor and LDL receptorrelated protein 1 (8). Other LPL activators include apo AIV (6) and apo AV (9, 10). Angiopoietin-like protein 3 (ANGPTL3) produced by the liver inhibits LPL in peripheral tissues in an endocrine fashion (4, 11), whereas ANGPTL4, which is produced in several tissues (4), inhibits LPL in a paracrine fashion (4), thereby retarding clearance of the triglyceride-rich lipoproteins (4). Angiopoietin-like protein 8 also plays a role in inhibiting LPL and seems to facilitate the ability of ANGPTL3 to inhibit LPL (1214). The clearance of triglycerides from plasma is saturable when plasma triglyceride levels exceed approximately 5.65 to 7.91 mmol/L (500 to 700 mg/dL) (15); the result is that additional chylomicrons and VLDL entering plasma cannot readily be removed, hence they accumulate. Under these circumstances, plasma triglyceride levels may increase dramatically, resulting in very high levels and chylomicron accumulation in plasma obtained after an overnight fast (Figure 1). Measuring chylomicrons in fasted plasma requires techniques that determine apo B48 in fractions of plasma isolated by ultracentrifugation (16), which are impractical for routine clinical use. For everyday purposes, some chylomicrons probably are present in anyone with a triglyceride level above 11.30 mmol/L (1000 mg/dL) (17). Figure 1. Pathophysiology of severe hypertriglyceridemia. Km= Michaelis constant; VLDL= very-low-density lipoprotein; Vmax= maximum velocity. Top. When triglyceride removal mechanisms are not saturated (central graph), outflow from plasma equals inflow and plasma triglyceride levels are stable, as depicted by the level in the sink. Bottom. When increased hepatic input of VLDL leads to saturation of triglyceride removal mechanisms, inflow from VLDL and chylomicrons exceeds outflow, leading to a marked increase in the plasma triglyceride pool, depicted as the overflowing sink. Causes of the Chylomicronemia Syndrome Conditions that may elevate triglyceride levels sufficiently to result in features of the chylomicronemia syndrome are classified in 3 major groups: monogenic FCS, multifactorial chylomicronemia syndrome (MFCS), and familial partial lipodystrophy (FPLD). FCS Familial chylomicronemia syndrome, originally called type 1 hyperlipoproteinemia (2) and later, primary LPL deficiency (18), is characterized by accumulation of chylomicrons. As mutations in other proteins involved in the clearance of triglycerides from plasma were discovered, the term FCS came into use. Familial chylomicronemia syndrome is an autosomal recessive disorder, the causes of which include nonfunctioning LPL mutations (1921), loss-of-function mutations in apo CII (22, 23) and apo AV (22, 24, 25), and mutations leading to defective or absent GPIHBP1 (22, 26) and LMF1 (6). Mutations in any of these proteins impair the clearance of chylomicrons and VLDL from plasma. Of interest, gain-of-function mutations in ANGPTLs causing FCS have not been described to date. In one study, LPL mutations accounted for most FCS cases, with mutations in apo CII and GPIHBP1 being the next most common (27). Early onset of chylomicronemia is very suggestive of FCS. The frequency of FCS is estimated to be approximately 1 in 1 million in most populations (25); therefore, it is very rare. A diagnosis can be made by the absence of LPL activity in plasma after the injection of heparin, but LPL activity assays are not widely available and may be difficult to interpret because of variability among assays. A more modern molecular genetic approach based on DNA sequencing, provides specific information regarding the mutant gene, but is not widely available, is expensive, and is seldom covered by insurance in the United States. Moreover, mutations in other proteins resulting in FCS probably will be discovered in the future. MFCS A much more common cause of the chylomicronemia syndrome is MFCS. The terms type 5 hyperlipoproteinemia (2) and polygenic late-onset chylomicronemia (28) probably describe the same group of diseases. In our early experience, MFCS nearly always resulted from the coexistence of a genetic predisposition to hypertriglyceridemia with 1 or more secondary causes of hypertriglyceridemia (29). In index cases of severe hypertriglyceridemia, patients had triglyceride levels far higher than their first-degree relatives with hypertriglyceridemia (29). Several of these patients were classified as having either familial hypertriglyceridemia or familial combined hyperlipidemia, both of which were initially thought to be monogenic disorders (30). However, common mild to moderate forms of hypertriglyceridemia have been shown to be typically polygenic and to result from the cumulative burden of common and rare variants in more than 30 genes (28). The resulting genetic hypertriglyceridemia may be exacerbated by nongenetic factors (28) or age (31). The presence of a secondary form or forms of hypertriglyceridemia against such a genetic background may saturate the triglyceride clearance me