Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome-Causes, Clinical Presentation, and Therapeutic Options

Abstract

We have reviewed the genetic basis of chylomicronaemia, the difference between monogenic and polygenic hypertriglyceridaemia, its effects on pancreatic, cardiovascular, and microvascular complications, and current and potential future pharmacotherapies. Severe hypertriglyceridaemia (TG > 10 mmol/L or 1000 mg/dL) is rare with a prevalence of <1%. It has a complex genetic basis. In some individuals, the inheritance of a single rare variant with a large effect size leads to severe hypertriglyceridaemia and fasting chylomicronaemia of monogenic origin, termed as familial chylomicronaemia syndrome (FCS). Alternatively, the accumulation of multiple low-effect variants causes polygenic hypertriglyceridaemia, which increases the tendency to develop fasting chylomicronaemia in presence of acquired factors, termed as multifactorial chylomicronaemia syndrome (MCS). FCS is an autosomal recessive disease characterized by a pathogenic variant of the lipoprotein lipase (LPL) gene or one of its regulators. The risk of pancreatic complications and associated morbidity and mortality are higher in FCS than in MCS. FCS has a more favourable cardiometabolic profile and a low prevalence of atherosclerotic cardiovascular disease (ASCVD) compared to MCS. The cornerstone of the management of severe hypertriglyceridaemia is a very-low-fat diet. FCS does not respond to traditional lipid-lowering therapies. Several novel pharmacotherapeutic agents are in various phases of development. Data on the correlation between genotype and phenotype in FCS are scarce. Further research to investigate the impact of individual gene variants on the natural history of the disease, and its link with ASCVD, microvascular disease, and acute or recurrent pancreatitis, is warranted. Volanesorsen reduces triglyceride concentration and frequency of pancreatitis effectively in patients with FCS and MCS. Several other therapeutic agents are in development. Understanding the natural history of FCS and MCS is necessary to rationalise healthcare resources and decide when to deploy these high-cost low-volume therapeutic agents.

Keywords: atherosclerosis; chylomicronaemia syndrome; hypertriglyceridaemia; microvascular complications; pancreatitis; volanesorsen.

Figure 1

(a) Dietary TGs and cholesterol are hydrolysed by lingual, gastric, pancreatic, and intestinal lipases into free fatty acids (FFA) and glycerol that are transported from the intestinal lumen to enterocytes where they are re-esterified and packaged into the transport cargo, chylomicrons. These enter circulation via the lymphatic system (the thoracic duct) and, thence, to the subclavian vein. In the systemic circulation, TG in chylomicrons is hydrolysed by lipoprotein lipase (LPL) which is expressed in high concentrations on the capillary surface of muscle and adipose tissue. Continuous hydrolysis of TG in chylomicron particles reduces its size and transfers apolipoproteins from the chylomicron surface to other lipoproteins while retaining ApoB48 and ApoE. Remnant particles undergo hepatic clearance, primarily involving LDL receptors, LDL receptor-related protein-1 (LRP-1), and heparan sulphate proteoglycans (syndecan 1). ApoE is important for this receptor-mediated uptake and clearance of chylomicron remnants, the failure of which leads to diminished chylomicron clearance and resultant hypertriglyceridaemia (as seen in dysbetalipoproteinaemia). CR and other TRL can penetrate the vascular endothelium and, unlike LDL, can be taken up by macrophages directly without chemical modification, hence contributing to atherogenesis. CETP facilitates the transfer of CE from HDL to TRL and TG from TRL to HDL. LDL represents major circulatory cholesterol and is delivered to most of the tissues and liver via the LDL receptor. Excess cholesterol is removed from cells via HDL and is transferred either to other lipoprotein subfractions or directly to the liver. Adapted from Bhatnagar D, Soran H, Durrington PN. Hypercholesterolaemia and its management [7]. (b) Dietary fat is absorbed from the intestine and assembled in chylomicrons. Hydrolysis of TG by LPL expressed on the capillary surface of fat and muscle cells leads to the production of CR that are taken up by the liver. The liver produces TRL that undergoes hydrolysis by LPL, leading to a progressive reduction in its size with loss of TG from its core, leading to the production of IDL and LDL. LMF1is a membrane-spanning protein that is responsible for the maturation, stabilisation, and transport of LPL to the capillary endothelial surface. GPIHBP1 binds LPL from the subendothelial interstitial space, transporting and anchoring it to the luminal surface of vascular endothelial cells. ApoC2 acquired from HDL acts as an activator of LPL and is important in regulating LPL activity and chylomicron catabolism. ApoA5 acts as an activator of LPL and the loss of function of ApoA5 leads to reduced LPL activity. ApoC3 inhibits LPL activity and apoE-mediated hepatic uptake of chylomicron and VLDL remnants. ANGPLT3 inhibits LPL activity. ABCA1: ATP-binding cassette transporter protein 1; ABCG1: ATP-binding cassette transporter member 1 of subfamily G; ANGPTL3: angiopoietin-like 3; Apo: apolipoprotein; CE: cholesteryl ester; CETP: cholesteryl ester transfer protein; CR: chylomicron remnants; FFA: free fatty acids; GPIHBP1: glycosylphosphatidylinositol-anchored HDL-binding protein1; HDL, high-density lipoprotein; IDL: intermediate-density lipoprotein; LDL: low-density lipoprotein; LPL: lipoprotein lipase; LMF1: lipase maturation factor 1; LRP, lipoprotein-related receptor; TG: triglycerides; TRL: triglyceride-rich lipoproteins; VLDL: very-low-density lipoprotein; VLDL, very-low-density lipoprotein.

Figure 1

(a) Dietary TGs and cholesterol are hydrolysed by lingual, gastric, pancreatic, and intestinal lipases into free fatty acids (FFA) and glycerol that are transported from the intestinal lumen to enterocytes where they are re-esterified and packaged into the transport cargo, chylomicrons. These enter circulation via the lymphatic system (the thoracic duct) and, thence, to the subclavian vein. In the systemic circulation, TG in chylomicrons is hydrolysed by lipoprotein lipase (LPL) which is expressed in high concentrations on the capillary surface of muscle and adipose tissue. Continuous hydrolysis of TG in chylomicron particles reduces its size and transfers apolipoproteins from the chylomicron surface to other lipoproteins while retaining ApoB48 and ApoE. Remnant particles undergo hepatic clearance, primarily involving LDL receptors, LDL receptor-related protein-1 (LRP-1), and heparan sulphate proteoglycans (syndecan 1). ApoE is important for this receptor-mediated uptake and clearance of chylomicron remnants, the failure of which leads to diminished chylomicron clearance and resultant hypertriglyceridaemia (as seen in dysbetalipoproteinaemia). CR and other TRL can penetrate the vascular endothelium and, unlike LDL, can be taken up by macrophages directly without chemical modification, hence contributing to atherogenesis. CETP facilitates the transfer of CE from HDL to TRL and TG from TRL to HDL. LDL represents major circulatory cholesterol and is delivered to most of the tissues and liver via the LDL receptor. Excess cholesterol is removed from cells via HDL and is transferred either to other lipoprotein subfractions or directly to the liver. Adapted from Bhatnagar D, Soran H, Durrington PN. Hypercholesterolaemia and its management [7]. (b) Dietary fat is absorbed from the intestine and assembled in chylomicrons. Hydrolysis of TG by LPL expressed on the capillary surface of fat and muscle cells leads to the production of CR that are taken up by the liver. The liver produces TRL that undergoes hydrolysis by LPL, leading to a progressive reduction in its size with loss of TG from its core, leading to the production of IDL and LDL. LMF1is a membrane-spanning protein that is responsible for the maturation, stabilisation, and transport of LPL to the capillary endothelial surface. GPIHBP1 binds LPL from the subendothelial interstitial space, transporting and anchoring it to the luminal surface of vascular endothelial cells. ApoC2 acquired from HDL acts as an activator of LPL and is important in regulating LPL activity and chylomicron catabolism. ApoA5 acts as an activator of LPL and the loss of function of ApoA5 leads to reduced LPL activity. ApoC3 inhibits LPL activity and apoE-mediated hepatic uptake of chylomicron and VLDL remnants. ANGPLT3 inhibits LPL activity. ABCA1: ATP-binding cassette transporter protein 1; ABCG1: ATP-binding cassette transporter member 1 of subfamily G; ANGPTL3: angiopoietin-like 3; Apo: apolipoprotein; CE: cholesteryl ester; CETP: cholesteryl ester transfer protein; CR: chylomicron remnants; FFA: free fatty acids; GPIHBP1: glycosylphosphatidylinositol-anchored HDL-binding protein1; HDL, high-density lipoprotein; IDL: intermediate-density lipoprotein; LDL: low-density lipoprotein; LPL: lipoprotein lipase; LMF1: lipase maturation factor 1; LRP, lipoprotein-related receptor; TG: triglycerides; TRL: triglyceride-rich lipoproteins; VLDL: very-low-density lipoprotein; VLDL, very-low-density lipoprotein.

Figure 2

Scoring of familial chylomicronaemia syndrome, according to Moulin et al. [17]. Adapted from: Moulin P., Dufour R., Averna M. et al.: Identification and Diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an “FCS Score”; Atherosclerosis 2018; DOI: 10.1016/j.atherosclerosis.2018.06.814 [18]. ^a Plasma triglyceride concentrations measured at least one month apart. ^b Secondary factors include alcohol, diabetes, metabolic syndrome, hypothyroidism, corticotherapy, and additional drugs. ^c If diagnosis is made during pregnancy, a second assessment is necessary to confirm diagnosis post-partum.

Figure 3

The exocrine pancreas is a rich source of pancreatic lipases that result in the hydrolysis of TG, resulting in the liberation of a large amount of free fatty acids that, once exceeding the binding capacity of albumin, leads to mitochondrial toxicity, oxidative stress, and creates proinflammatory milieu and acinar cell damage, culminating in pancreatic acinar necrosis. In addition, chylomicronaemia and free fatty acids via micelle formation increase the viscosity of blood and, thereby, impede the blood flow to the pancreas, leading to ischemia and worsening acidosis, which potentiates FFA-mediated acinar cell damage. A certain amount of pancreatic lipase, rather than entering the lumen of the gut, finds its way into the capillary circulation of the pancreas. Normally, this does not matter. However, when the pancreatic microcirculation is sluggish in chylomicronaemia, there is time for it to release fatty acids and lysolipids, which are cytotoxic [22,58,59]. ER: endoplasmic reticulum; NO: nitric oxide; PGI2: prostacyclin I2; ROS: reactive oxygen species; TXA2: thromboxane A2.

Figure 4

Algorithm for management of hypertriglyceridaemia-induced acute pancreatitis. ^a serum amylase can be inaccurate or normal in HTGP due to lipaemia. ^b aim to keep CBG between 6.0–10.0 mmol/L. ^c seek specialist advice before stopping long-term medications. ^d seek a specialist to advise; decision should be individualised. No evidence of benefit in terms of hard clinical outcomes, i.e., mortality, the severity of pancreatitis, length of hospital stay, and complications. AP: acute pancreatitis; APACHE II: The Acute Physiology and Chronic Health Examination; CTSI: CT severity index; HDU: high-dependency unit; HTG: hypertriglyceridaemia; HTGP: hypertriglyceridaemia-induced pancreatitis; ITU: intensive therapy unit; NBM: nil by mouth; SHTG: severe hypertriglyceridaemia; TG, Triglycerides; VRII: variable-rate insulin infusion.

Figure 5

A possible algorithm for diagnosis and management of severe hypertriglyceridaemia. ASCVD: atherosclerotic cardiovascular disease; CV: cardiovascular; FCS: familial chylomicronaemia syndrome; MCS: multifactorial chylomicronaemia syndrome; O3FA: omega-3 fatty acids; VUS: variant of unknown significance.