- Email: [email protected]
From the Editor: Learning from defects
Journal of Clinical Lipidology (2013) 7, 91–92
Foreword
From the Editor: Learning from defects The Journal of Clinical Lipidology has attempted to maintain its focus on lipoprotein disorders in humans by emphasizing clinical management but also cultivating a strong interest in the disorders of lipid metabolism that contain lessons regarding pathophysiology. The current issue contains demonstrative studies of deranged physiology that are attributable to genetic defects in patients. These articles teach lessons and answer questions that laboratory or animal experiments cannot adequately address. When the clinical presentations are studied in an imaginative manner, the information derived can lead to strong affirmation or to serious challenges to current theory of disease. This month the Journal contains ‘‘experiments of nature’’ produced by variants in the genes for apolipoproteins AI, A5, and E; the low-density lipoprotein (LDL) receptor; lipoprotein lipase; and the Niemann-Pick C1 Like 1 (NPC1-L1) cholesterol transporter. Lee et al report the clinical presentation of a 61-year-old man who was diagnosed with coronary artery disease at 41 years of age while having a high-density cholesterol (HDL) count of less than 5 mg/dL. The defect was defined as an insertion into one allele of apolipoprotein AI, which apparently led to rapid clearance of HDL in general. The fact that the patient was apparently well until middle age even though he had multiple other risk factors, including high blood pressure, obesity, high triglycerides, increased total cholesterol, and cigarette smoking, again highlights the complex relationships of HDL with the etiology of atherosclerosis. Variants in the gene for the NPC1-L1 cholesterol transporter have been associated with both reduced cholesterol absorption and with evidence for increased absorption. One of these, involving the substitution of cytosine for guanine at position 816 in the gene, was previously shown to be a marker for enhanced responsiveness to the NPC1-L1 inhibitor ezetimibe. Lupatelli et al report that this genetic alteration appears to be linked to enhanced cholesterol absorption because sterol absorption (including cholesterol absorption), is significantly greater in patients with increased cholesterol levels. When this methodology was used, the authors found that the association of apolipoprotein E4 isoform also was linked to significantly greater absorption and that there was an interaction between the presence of the E4 protein and
the NPC1-L1 variant. Previous investigators have produced variable results regarding the effects of apolipoprotein E on cholesterol absorption, but this is one of the largest studies of this issue and seems to confirm a significant enhanced absorption of dietary sterols when the E4 variant is present. Apolipoprotein A5 is produced in the liver and is believed to be delivered to the endothelium by newly formed triglyceride-rich lipoproteins. It appears to be among several crucial facilitators of lipoprotein lipase action and is negatively correlated with triglyceride concentrations. However, a variant in the promoter region of the gene appears to impact the plasma concentrations of this protein and correlate positively with triglyceride concentrations. This finding suggests dysfunction in the clearance of very-low-density lipoprotein but might be related to enhanced synthesis of triglyceride-rich lipoproteins. This article discusses the complex nature of apolipoprotein A5 and the need for further studies to fully understand its functionality in lipoprotein metabolism. The treatment of lipoprotein lipase deficiency customarily has involved the prescription of a very low-fat diet and the addition of medium-chain triglycerides for use in food preparation. The full success of this therapy is often lacking. Patients will, on occasion, yield to temptation and consume a significantly fatty meal. In this disorder, a departure from the prescribed diet can lead to pancreatitis and hospitalization with an abdominal crisis. Blackett et al report in this issue of the Journal their observations of 2 cases with lipoprotein lipase deficiency attributable to well-characterized but different mutations in both alleles of the gene, both in exon 5. These siblings, ages 9 and 6 years, originally presented with triglycerides well above 10,000 mg/dL. With usual therapy, most plasma triglyceride values remained greater than 2000 mg/dL until the pancreatic lipase inhibitor, orlistat was introduced; subsequently, values well below 1000 were maintained. Orlistat has been used in adults with other forms of hypertriglyceridemia but this is believed to be the first demonstration that it can have a positive impact in patients with lipoprotein lipase deficiency. The gene sequence abnormalities that produce the LDL elevations and clinical findings of familial hypercholesterolemia are possibly the most thoroughly studied of all genetic disorders affecting humankind. These involve
1933-2874/$ - see front matter Ó 2013 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2013.01.002
92 apolipoprotein B, proprotein convertase subtilisin/kexin-like 9, and, most commonly, the LDL receptor genes. Defects in the latter now number in the thousands. Feddersen et al report on 3 Danish families that have a rare exon duplication in the LDL receptor that produces this syndrome, but most importantly these authors describe the process of gene screening and its potential advantages in the understanding and management of familial hypercholesterolemia. Because the clinical syndrome is now so well defined and criteria have been spelled out by our colleagues in the Netherlands, many believe that this added expense is not necessary. However, these authors argue that the determination of gene
Journal of Clinical Lipidology, Vol 7, No 2, April 2013 sequences will become very inexpensive, and even with marginal clinical value combined with the understanding of the inheritance, may well result in this practice becoming a very common one in the future. W. Virgil Brown, MD Editor-in-Chief Charles Howard Candler Professor of Medicine Emeritus Emory University School of Medicine Atlanta, GA E-mail address: [email protected]
Foreword
From the Editor: Learning from defects The Journal of Clinical Lipidology has attempted to maintain its focus on lipoprotein disorders in humans by emphasizing clinical management but also cultivating a strong interest in the disorders of lipid metabolism that contain lessons regarding pathophysiology. The current issue contains demonstrative studies of deranged physiology that are attributable to genetic defects in patients. These articles teach lessons and answer questions that laboratory or animal experiments cannot adequately address. When the clinical presentations are studied in an imaginative manner, the information derived can lead to strong affirmation or to serious challenges to current theory of disease. This month the Journal contains ‘‘experiments of nature’’ produced by variants in the genes for apolipoproteins AI, A5, and E; the low-density lipoprotein (LDL) receptor; lipoprotein lipase; and the Niemann-Pick C1 Like 1 (NPC1-L1) cholesterol transporter. Lee et al report the clinical presentation of a 61-year-old man who was diagnosed with coronary artery disease at 41 years of age while having a high-density cholesterol (HDL) count of less than 5 mg/dL. The defect was defined as an insertion into one allele of apolipoprotein AI, which apparently led to rapid clearance of HDL in general. The fact that the patient was apparently well until middle age even though he had multiple other risk factors, including high blood pressure, obesity, high triglycerides, increased total cholesterol, and cigarette smoking, again highlights the complex relationships of HDL with the etiology of atherosclerosis. Variants in the gene for the NPC1-L1 cholesterol transporter have been associated with both reduced cholesterol absorption and with evidence for increased absorption. One of these, involving the substitution of cytosine for guanine at position 816 in the gene, was previously shown to be a marker for enhanced responsiveness to the NPC1-L1 inhibitor ezetimibe. Lupatelli et al report that this genetic alteration appears to be linked to enhanced cholesterol absorption because sterol absorption (including cholesterol absorption), is significantly greater in patients with increased cholesterol levels. When this methodology was used, the authors found that the association of apolipoprotein E4 isoform also was linked to significantly greater absorption and that there was an interaction between the presence of the E4 protein and
the NPC1-L1 variant. Previous investigators have produced variable results regarding the effects of apolipoprotein E on cholesterol absorption, but this is one of the largest studies of this issue and seems to confirm a significant enhanced absorption of dietary sterols when the E4 variant is present. Apolipoprotein A5 is produced in the liver and is believed to be delivered to the endothelium by newly formed triglyceride-rich lipoproteins. It appears to be among several crucial facilitators of lipoprotein lipase action and is negatively correlated with triglyceride concentrations. However, a variant in the promoter region of the gene appears to impact the plasma concentrations of this protein and correlate positively with triglyceride concentrations. This finding suggests dysfunction in the clearance of very-low-density lipoprotein but might be related to enhanced synthesis of triglyceride-rich lipoproteins. This article discusses the complex nature of apolipoprotein A5 and the need for further studies to fully understand its functionality in lipoprotein metabolism. The treatment of lipoprotein lipase deficiency customarily has involved the prescription of a very low-fat diet and the addition of medium-chain triglycerides for use in food preparation. The full success of this therapy is often lacking. Patients will, on occasion, yield to temptation and consume a significantly fatty meal. In this disorder, a departure from the prescribed diet can lead to pancreatitis and hospitalization with an abdominal crisis. Blackett et al report in this issue of the Journal their observations of 2 cases with lipoprotein lipase deficiency attributable to well-characterized but different mutations in both alleles of the gene, both in exon 5. These siblings, ages 9 and 6 years, originally presented with triglycerides well above 10,000 mg/dL. With usual therapy, most plasma triglyceride values remained greater than 2000 mg/dL until the pancreatic lipase inhibitor, orlistat was introduced; subsequently, values well below 1000 were maintained. Orlistat has been used in adults with other forms of hypertriglyceridemia but this is believed to be the first demonstration that it can have a positive impact in patients with lipoprotein lipase deficiency. The gene sequence abnormalities that produce the LDL elevations and clinical findings of familial hypercholesterolemia are possibly the most thoroughly studied of all genetic disorders affecting humankind. These involve
1933-2874/$ - see front matter Ó 2013 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2013.01.002
92 apolipoprotein B, proprotein convertase subtilisin/kexin-like 9, and, most commonly, the LDL receptor genes. Defects in the latter now number in the thousands. Feddersen et al report on 3 Danish families that have a rare exon duplication in the LDL receptor that produces this syndrome, but most importantly these authors describe the process of gene screening and its potential advantages in the understanding and management of familial hypercholesterolemia. Because the clinical syndrome is now so well defined and criteria have been spelled out by our colleagues in the Netherlands, many believe that this added expense is not necessary. However, these authors argue that the determination of gene
Journal of Clinical Lipidology, Vol 7, No 2, April 2013 sequences will become very inexpensive, and even with marginal clinical value combined with the understanding of the inheritance, may well result in this practice becoming a very common one in the future. W. Virgil Brown, MD Editor-in-Chief Charles Howard Candler Professor of Medicine Emeritus Emory University School of Medicine Atlanta, GA E-mail address: [email protected]