Familial hypertriglyceridemia

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Familial hypertriglyceridemia
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Familial hypertriglyceridemia is inherited in autosomal dominant manner

Familial hypertriglyceridemia (type IV familial dyslipidemia) is a genetic disorder characterized by the liver overproducing very-low-density lipoproteins (VLDL). As a result, an affected individual will have an excessive number of VLDL and triglycerides on a lipid profile. This genetic disorder usually follows an autosomal dominant inheritance pattern. The disorder presents clinically in patients with mild to moderate elevations in triglyceride levels. Familial hypertriglyceridemia is typically associated with other co-morbid conditions such as hypertension, obesity, and hyperglycemia. Individuals with the disorder are mostly heterozygous in an inactivating mutation of the gene encoding for lipoprotein lipase (LPL). This sole mutation can markedly elevate serum triglyceride levels. However, when combined with other medications or pathologies it can further elevate serum triglyceride levels to pathologic levels. [1] Substantial increases in serum triglyceride levels can lead to certain clinical signs and the development of acute pancreatitis.

Contents

Familial hypertriglyceridemia falls in the Fredrickson-Levy and Lee's (FLL) phenotypes. The phenotypes include types I, IIa, IIb, III, IV, and V dyslipidemias. Familial hypertriglyceridemia is considered a type IV familial dyslipidemia it is distinguished from other dyslipidemias based on the individual's lipid profile. Familial hypertriglyceridemia separates itself from other dyslipidemias with significantly high triglycerides and low HDL levels. It is important to recognize that co-morbid conditions that often concomitantly exist with the disorder can further alter the lipid panel. [2]

Presentation

Etiology

Familial hypertriglyceridemia is considered to be inherited in an autosomal dominant manner. However, it is important to recognize that most cases have a polygenic inheritance distancing themselves from traditional Mendelian inheritance patterns. [3] One of the most common mutations implicated in the development of familial hypertriglyceridemia is a heterozygous inactivating mutation of the LPL gene. Inactivation of this gene leads to an individual's inability to hydrolyze the triglycerides within the VLDL core. This inactivation of function leads to a considerable accumulation of triglycerides and VLDL in the bloodstream, which then contributes to several avenues of pathology. Individuals with insulin resistance can have even further elevated levels of hypertriglyceridemia due to the fact that insulin is a potent activator of LPL. Therefore, an individual who is resistant to the bioactivity of insulin will have decreased LPL activity and will therefore lead to further hypertriglyceridemia, helping push serum triglycerides to pathologic levels. Beyond the classic understanding of single-gene mutation leading to disease, hypertriglyceridemia is also linked to several different genetic loci permitting additional aberrant changes to other lipid levels in the body. [4]

Pathophysiology

Inactivity of lipoprotein lipase (LPL) plays the predominant role in the development of familial hypertriglyceridemia. LPL plays a role in the metabolism of triglycerides within VLDL molecules. Inactivation mutations in LPL will create an environment with an increased concentration of VLDL molecules and therefore, triglycerides. The elevation of baseline triglyceride levels begins the cascade into other pathologies. [2]

The most common acute manifestation of hypertriglyceridemia is the occurrence of pancreatitis. Pancreatitis is caused by the premature activation of exocrine pancreatic enzymes. Secreted zymogens are cleaved to active trypsin and play a central role in digestion of food in the duodenum. If there is premature activation of trypsin within the pancreatic tissues, there is an induction of autodigestion of local tissue which leads to the initial presentation of pancreatitis. Autodigestion of local tissues also leads to disruptions in pancreatic microvascular tissue which can cause an ischemia-reperfusion event at the pancreatic level. There are other varying secondary causes of pancreatitis that can further contribute to the primary scenario of pancreatitis related to familial hypertriglyceridemia. [5] [6]

Diagnosis

Treatment

Treatment for familial hypertriglyceridemia should focus primarily on reducing serum triglyceride levels. If an individual has co-morbid conditions, ensuring that they are adequately addressed will aid in obtaining a more normal baseline lipid panel. Current guidelines suggest that when evaluating individuals with familial hypertriglyceridemia there should be special attention paid to their risk of developing cardiovascular disease in individuals with mild to moderate hypertriglyceridemia. Individuals with severe hypertriglyceridemia should be promptly evaluated for the possibility of developing pancreatitis. [5] The initial treatment for severe hypertriglyceridemia consists of beginning an individual on fibrate therapy in an attempt to normalize triglyceride levels. Fibrates such as fenofibrate or gemfibrozil are considered first-line therapy for the disease. Adjunctive niacin therapy can be used for individuals who are unable to decrease triglyceride levels through fibrate monotherapy. Niacin is especially useful for individuals who have a high risk of getting pancreatitis. A fish oil supplement can also be used as it has been shown to incur a significant reduction to both triglyceride and VLDL levels. [7] If properly managed, individuals with familial hypertriglyceridemia have a fairly good prognosis. If therapy is successful, these individuals do not have uncontrolled severe triglycerides and VLDL. It is important to educate individuals on possible secondary causes of elevated lipid profiles. Proper management of the secondary causes provides a good prognosis for overall individual health.[ citation needed ]

Epidemiology

Familial hypertriglyceridemia can follow an autosomal dominant monogenic inheritance pattern. The frequency of heterozygous carriers of certain pathologic mutations in the LPL gene can range from 0.06% to 20%. It is important to note that dissimilar mutations can confer varying degrees of underlying pathology. However, most cases of familial hypertriglyceridemia follow a polygenic inheritance pattern involving mutations in multiple genetic foci. [8] [9]

See also

Related Research Articles

<span class="mw-page-title-main">Lipoprotein</span> Biochemical assembly whose purpose is to transport hydrophobic lipid molecules

A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.

<span class="mw-page-title-main">Fibrate</span> Class of chemical compounds

In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.

Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins. VLDL is converted in the bloodstream to low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL). VLDL particles have a diameter of 30–80 nanometers (nm). VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. In the early 2010s both the lipid composition and protein composition of this lipoprotein were characterised in great detail.

<span class="mw-page-title-main">Hypercholesterolemia</span> High levels of cholesterol in the blood

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases, which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for cardiovascular disease, abnormal levels do not mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia.

<span class="mw-page-title-main">Chylomicron</span> One of the five major groups of lipoprotein

Chylomicrons, also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85–92%), phospholipids (6–12%), cholesterol (1–3%), and proteins (1–2%). They transport dietary lipids, such as fats and cholesterol, from the intestines to other locations in the body, within the water-based solution of the bloodstream. ULDLs are one of the five major groups lipoproteins are divided into based on their density. A protein specific to chylomicrons is ApoB48.

<span class="mw-page-title-main">Hypertriglyceridemia</span> High triglyceride blood levels

Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and high triglyceride levels are associated with atherosclerosis, even in the absence of hypercholesterolemia and predispose to cardiovascular disease.

<span class="mw-page-title-main">Combined hyperlipidemia</span> Medical condition

Combined hyperlipidemia is a commonly occurring form of hypercholesterolemia characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electrophoresis it shows as a hyperlipoproteinemia type IIB. It is the most commonly inherited lipid disorder, occurring in around one in 200 persons. In fact, almost one in five individuals who develop coronary heart disease before the age of 60 have this disorder.

<span class="mw-page-title-main">Gemfibrozil</span> Medication

Gemfibrozil, sold under the brand name Lopid among others, is a medication used to treat abnormal blood lipid levels. It is generally less preferred than statins. Use is recommended together with dietary changes and exercise. It is unclear if it changes the risk of heart disease. It is taken by mouth.

<span class="mw-page-title-main">Lipoprotein lipase</span> Mammalian protein found in Homo sapiens

Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule:

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Cholesteryl ester transfer protein</span> Mammalian protein found in Homo sapiens

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.

<span class="mw-page-title-main">Fenofibrate</span> Drug of the fibrate class, mainly used to reduce cholesterol levels

Fenofibrate (sold under the brand name Tricor among others, is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein cholesterol. Its use is recommended together with dietary changes.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

Lecithin cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism. The disease has two forms: Familial LCAT deficiency, in which there is complete LCAT deficiency, and Fish-eye disease, in which there is a partial deficiency.

<span class="mw-page-title-main">Apolipoprotein C-III</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.

<span class="mw-page-title-main">Lipoprotein lipase deficiency</span> Genetic disorder in fat handling

Lipoprotein lipase deficiency is a genetic disorder in which a person has a defective gene for lipoprotein lipase, which leads to very high triglycerides, which in turn causes stomach pain and deposits of fat under the skin, and which can lead to problems with the pancreas and liver, which in turn can lead to diabetes. The disorder only occurs if a child acquires the defective gene from both parents. It is managed by restricting fat in diet to less than 20 g/day.

Blood lipids are lipids in the blood, either free or bound to other molecules. They are mostly transported in a phospholipid capsule, and the type of protein embedded in this outer shell determines the fate of the particle and its influence on metabolism. Examples of these lipids include cholesterol and triglycerides. The concentration of blood lipids depends on intake and excretion from the intestine, and uptake and secretion from cells. Hyperlipidemia is the presence of elevated or abnormal levels of lipids and/or lipoproteins in the blood, and is a major risk factor for cardiovascular disease.

<span class="mw-page-title-main">APOA5</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

A lipid profile or lipid panel is a panel of blood tests used to find abnormalities in blood lipid concentrations. The results of this test can identify certain genetic diseases and can determine approximate risks for cardiovascular disease, certain forms of pancreatitis, and other diseases.

References

  1. ↑ Ripatti P, Rämö JT, Mars NJ, Fu Y, Lin J, Söderlund S, et al. (April 2020). "Polygenic Hyperlipidemias and Coronary Artery Disease Risk". Circulation: Genomic and Precision Medicine. 13 (2): e002725. doi:10.1161/CIRCGEN.119.002725. PMC   7176338 . PMID   32154731.
  2. 1 2 Quispe R, Hendrani A, Baradaran-Noveiry B, Martin S, Brown E, Kulkarni K, et al. (2019). "Characterization of lipoprotein profiles in patients with hypertriglyceridemic Fredrickson-Levy and Lees dyslipidemia phenotypes: the Very Large Database of Lipids Studies 6 and 7". Archives of Medical Science. 15 (5): 1195–1202. doi:10.5114/aoms.2019.87207. PMC   6764300 . PMID   31572464. S2CID   203620865.
  3. ↑ Hegele RA, Ban MR, Hsueh N, Kennedy BA, Cao H, Zou GY, et al. (1 November 2009). "A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia". Human Molecular Genetics. 18 (21): 4189–4194. doi:10.1093/hmg/ddp361. PMC   2758142 . PMID   19656773.
  4. ↑ Johansen CT, Wang J, Lanktree MB, McIntyre AD, Ban MR, Martins RA, et al. (August 2011). "An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (8): 1916–1926. doi:10.1161/ATVBAHA.111.226365. PMC   3562702 . PMID   21597005. S2CID   7920385.
  5. 1 2 Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. (1 September 2012). "Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology & Metabolism. 97 (9): 2969–2989. doi:10.1210/jc.2011-3213. PMC   3431581 . PMID   22962670.
  6. ↑ "Corrigenda". The Journal of Clinical Endocrinology & Metabolism. 100 (12): 4685. 1 December 2015. doi:10.1210/jc.2015-3649. PMC   5399508 . PMID   26562756.
  7. ↑ Pradhan A, Bhandari M, Vishwakarma P, Sethi R (March 2020). "Triglycerides and Cardiovascular Outcomes—Can We REDUCE-IT ?". International Journal of Angiology. 29 (1): 002–011. doi:10.1055/s-0040-1701639. PMC   7054063 . PMID   32132810.
  8. ↑ Triglyceride Coronary Disease Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, et al. (May 2010). "Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies". The Lancet. 375 (9726): 1634–1639. doi:10.1016/S0140-6736(10)60545-4. PMC   2867029 . PMID   20452521.
  9. ↑ "Department of Error". The Lancet. 376 (9735): 90. July 2010. doi:10.1016/S0140-6736(10)61075-6. PMC   3081093 .
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