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 A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and '' glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as ...

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 Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

, and

hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

. Individuals with the disorder are mostly

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

in an inactivating mutation of the gene encoding for

lipoprotein lipase 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-solubl ...

(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. Substantial increases in serum triglyceride levels can lead to certain clinical signs and the development of

acute pancreatitis Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes in order of frequency include: 1) a gallstone impacted in the common bile duct beyond the point where the pancreatic duct joins it; 2) heavy alcohol use; 3) systemic diseas ...

. Familial hypertriglyceridemia falls in the Fredrickson-Levy and Lee's (FLL)

phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...

. 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.

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 A quantitative trait locus (QTL) is a locus (section of DNA) that correlates with variation of a quantitative trait in the phenotype of a population of organisms. QTLs are mapped by identifying which molecular markers (such as SNPs or AFLPs) ...

distancing themselves from traditional

Mendelian inheritance Mendelian inheritance (also known as Mendelism) is a type of biological inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and later populari ...

patterns. 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 Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood suga ...

can have even further elevated levels of hypertriglyceridemia due to the fact that

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabol ...

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.

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.

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. The most common acute manifestation of hypertriglyceridemia is the occurrence of

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic p ...

. Pancreatitis is caused by the premature activation of exocrine pancreatic enzymes. Secreted zymogens are cleaved to active

trypsin Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...

and play a central role in digestion of food in the

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine ...

. If there is premature activation of trypsin within the pancreatic tissues, there is an induction of

autodigestion In biology, autolysis, more commonly known as self-digestion, refers to the destruction of a cell through the action of its own enzymes. It may also refer to the digestion of an enzyme by another molecule of the same enzyme. The term derives from ...

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.

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 Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...

in individuals with mild to moderate hypertriglyceridemia. Individuals with severe hypertriglyceridemia should be promptly evaluated for the possibility of developing pancreatitis. 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. Fish oil supplement can also be used as it has been shown to incur a significant reduction to both triglyceride and VLDL levels. 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.

References

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