Lipoprotein Lipase Deficiency

Etiology

Lipoprotein lipase deficiency occurs due to the presence of the defective gene for lipoprotein lipase that leads to the reduction or complete absence of lipoprotein lipase enzyme activity. Pathogenic deletions, nonsense mutations, and splice-site variants lead to the formation of an abnormal LPL gene product that leads to absent or truncated LPL enzyme with a defective catalytic activity. More than 220 pathological variants, including 70 percent missense mutations, 18 percent nucleotide insertions and deletions, 10 percent nonsense mutations, and a few splice site variants, have been identified.[2][3]

Because lipoprotein lipase deficiency has an autosomal recessive pattern of inheritance, the risk of two heterozygote parents to have a child affected with lipoprotein lipase deficiency is 25 percent, and the risk of having a heterozygote child is 50 percent, with each pregnancy. Each of the siblings of an affected individual has a 25 percent chance of being homozygous, a 50 percent chance of being heterozygous(carrier), and a 25 percent chance of being unaffected.

Epidemiology

Lipoprotein lipase deficiency is a rare disorder. Its prevalence is approximately 1 in 1,000,000 in the general population. Two LPL mutations G118E and P207L cause complete loss of LPL activity in homozygotes and 50% loss in heterozygotes have been reported in Quebec, Canada. Most cases of lipoprotein lipase deficiency are identified in childhood, usually, before ten years of age, and 25 % of the affected patients are identified during the first year of life. However, some individuals may not develop symptoms until adulthood, like women may present for the first time during pregnancy.[1][4] Males and females are affected equally.

Pathophysiology

The lipoprotein lipase gene is mapped to human chromosome 8p22, divided into ten exons and encodes the enzyme lipoprotein lipase, which is expressed in the adipose tissues and muscles. Lipoprotein lipase (LPL), a 475-aminoacid enzyme, is involved in the hydrolysis of triglyceride-rich lipoproteins, mainly chylomicrons and very high-density lipoproteins (VLDL). The catalytic center of the enzyme has three amino acids, namely, Ser132, Asp156, His241.

LPL activity is regulated by several factors, such as hormones, non-esterified fatty acids, and apolipoproteins. Apo AV, apolipoprotein C-II, insulin, acylation stimulating protein increase the LPL activity, while apolipoprotein C-III and TNF-alpha decrease the LPL activity. After LPL is produced in adipose tissues and muscles, which are the two most important sites of production, it is secreted and translocated to the luminal surface of capillary endothelial cells of extrahepatic tissues. The dietary fat absorbed in the intestines is transported in the form of triglycerides by large lipoproteins, known as chylomicrons. Once the chylomicrons are released into the bloodstream, they receive a lipoprotein known as apolipoprotein C-II from high-density lipoproteins.

Apolipoprotein C-II is a cofactor for the lipoprotein lipase enzyme. The lipoprotein lipase recognizes apolipoprotein C-II and gets activated, which results in the breaking down of the chylomicrons and VLDL triglycerides to nonesterified free fatty acids and 2-monoacylglycerol to be stored as triglyceride in adipose tissues or used as an energy source in muscles.[5][6] Lipoprotein lipase is also required for maturation of small particles of high-density lipoproteins into larger particles.[7]

Most of the mutations in the lipoprotein lipase gene are located on exons 2, 5, and 6. The well-known mutations include the following

• Asn291Ser, located on Exon 6, AAT-->AGT. It is the most common mutation in Whites. It is present in 2 to 5 percent of the heterozygote carrier population among the Whites. It is associated with an increased risk of Alzheimer disease.[8]
• 93T-->G, located on the promotor. The G allele is the most common mutation seen in South African Black ethnicity (76.4 percent). The T allele is seen in Whites (1.7 percent).[9]
• Asp9Asn, located on Exon 2, GAC-->AAC. It is less common. (1.56 to 4.4 percent of the population). The homozygous mutation causes only a 20 percent decrease in lipoprotein lipase activity.[10]
• Gly188glu, located on wxon 5, GGG-->GAG. (0.06 percent of the population).[11] It leads to homozygous chylomicronemia, most common among French Canadians in Quebec. It is known to have the strongest link leading to an increased risk of coronary artery disease.[11]
• Ala221del, located on exon 5, 916gCT-->CT. It leads to homozygote chylomicronemia. It is the most common mutation in Japanese ethnicity, also known as LPL Arita.[12]
• Carriers of Asn291Ser or the combined mutation Asp9Asn/T93G are known to have an increased risk of preeclampsia.[13]
• Ser447sto, located on exon 9, TCA-->TGA. This is a gain of function mutation leading to an increase in LPL activity. It is associated with a 0.8 fold reduced risk of ischemic heart disease, maximum benefit to those using beta-blockers.[14] Carriers of this mutation have lower plasma triglyceride levels and higher high-density lipoprotein levels. Therefore they have a lower incidence of cardiovascular disease as compared to non-carriers of this mutation.[15]

A reduction or elimination of lipoprotein lipase enzyme activity prevents the break down of triglycerides. Therefore, there is an accumulation of the triglycerides in the blood and tissues, leading to the clinical manifestations of lipoprotein lipase deficiency.[1] In homozygous individuals, the serum triglyceride levels may reach 10,000 mg/dL or higher. In heterozygous individuals, the serum triglyceride levels may range between 200 to 750 mg/dL.

According to many studies, Lipoprotein lipase deficiency is known to have no atherogenic potential because it causes a low level of low-density lipoproteins. But some studies show that a defect in lipolysis can be a risk factor for premature atherosclerosis. These studies were based on other metabolic disturbances, which have been described as follows. Lipoprotein lipase deficiency also leads to increased serum triglycerides and low high-density lipoproteins. Also, the postprandial clearance of triglycerides is delayed, exposing them to lipoproteins, thus leading to oxidative damage. Even reverse cholesterol transport is impaired as the high-density lipoprotein has structural changes, leading to increased and faster clearance.[16][7] 

Thus the lipoprotein profile of the patients of lipoprotein lipase deficiency is similar to the postprandial profile in which atherogenic particles are produced, predisposing to atherosclerosis.[17] However, the association of atherogenesis with lipoprotein lipase deficiency remains debated.

History and Physical

Lipoprotein lipase deficiency usually presents with the following:

• Abdominal pain is the most common presentation and occurs due to acute pancreatitis, intensity varying from mild to incapacitating (mimicking acute abdomen). The attacks of acute pancreatitis are recurrent and usually culminate in chronic pancreatitis.[18] Although the mechanism of acute pancreatitis following hypertriglyceridemia in LPL enzyme deficiency is not fully understood, oral antioxidants reduce the frequency of pancreatitis episodes, implying the role of oxidant damage in causing acute pancreatitis.[19][20] The risk of acute pancreatitis is about 5% when the serum triglycerides reach 1000 mg/dL or higher, and 10% to 20% when the serum triglycerides reach 2000 mg/dL or higher.[21][22]
• Xanthomas - In about 50 % of the individuals with lipoprotein lipase deficiency, eruptive xanthomas, which are yellow papules of around 1 mm in size, appear mostly on the trunk, knees, buttocks, and extensor surfaces of arms. These may coalesce to form larger patches. The formation of xanthomas occurs as a result of extravascular phagocytosis of chylomicrons by macrophages and deposition in the skin. They happen when plasma triglyceride levels rise above 2000 mg/dL and disappear when the plasma triglyceride levels return to normal. They are painless unless exposed to repetitive abrasion.[1]
• Loss of appetite
• Nausea, vomiting
• Arthralgia
• Myalgia
• Hepatomegaly and splenomegaly occur as a result of markedly increased plasma triglyceride levels. The excessive chylomicrons in the bloodstream are ingested by macrophages(phagocytes), which then travel to the liver and spleen. The fatty cells accumulate in the liver and spleen, leading to an increase in their size.[1]
• Retinalis lipemia - the retinal arterioles, venules, and fundus appear pale-pink as a result of scattering of light by the large chylomicrons. This change is reversible, and the vision gets spared. Retinalis lipemia is seen when the plasma triglyceride levels rise above 2500 mg/dL. When the triglyceride levels are between 2500 and 3499 mg/dL, the peripheral vessels of the retina appear thin. At triglyceride levels of 3500 to 5000 mg/dL, the retinal vessels at the posterior pole appear creamy in color. At triglyceride levels above 5000 mg/dL, the retina appears salmon in color with the creamy appearance of the retinal venules and arteries.[23][24][1]
• Neuropsychiatric changes like mild cognitive dysfunction, depression, and memory loss have been reported. These changes are reversible.[25][5]

Infants may present additionally with the following:

• Abdominal pain which appears as colic
• Irritability
• Diarrhea
• Intestinal bleeding
• Pallor
• Seizures
• Failure to thrive[23]

In women, the presentation may be delayed until pregnancy. A woman with lipoprotein lipase deficiency may present with marked signs and symptoms during pregnancy due to increased uptake of triglyceride-rich lipoproteins by the macrophages, owing to the increased apolipoprotein E during pregnancy.[4]

The severity of the clinical presentation of lipoprotein lipase deficiency correlates with the chylomicron levels.

Evaluation

Lipoprotein lipase deficiency is suspected in young individuals with the following clinical findings in addition to the supportive laboratory findings.

Clinical Findings

1. Recurrent attacks of acute pancreatitis
2. Eruptive xanthoma
3. Hepatosplenomegaly
4. Retinalis lipemia

Lab Findings

1. Milky appearing plasma. This occurs due to the impaired clearance of the chylomicrons from the plasma.
2. Plasma triglyceride levels exceeding 2000 mg/dL. These levels are considered regardless of the fasting state.

Diagnosis

The diagnosis of lipoprotein lipase deficiency is established by molecular genetic testing, which identifies the proband by identifying the biallelic pathogenic variants in the lipoprotein lipase gene.[26] Two test methods are used, which include:

• Sequence analysis - This identifies 97 % of probands with the biallelic pathogenic variants.
• Gene targeted duplication/deletion analysis - this identifies 4% of probands with biallelic pathogenic variants.

Molecular genetic testing can be done for only lipoprotein lipase gene identification, or to identify the other four genes as well, which can lead to chylomicronemia. It is described as follows :

• Single gene testing - The sequence analysis of only the lipoprotein lipase gene is performed. If one or no pathogenic variant is found, the sequence analysis is followed by the gene-targeted duplication/deletion analysis.
• Multigene panel - It includes the lipoprotein lipase gene as well as of the other four genes, namely, apolipoprotein C- II gene, apolipoprotein A-V gene, lipase maturation factor 1 gene, and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein gene, for the chylomicronemia syndrome. Sequence analysis and gene-targeted duplication/deletion, any method may be used.[1][26]

Measurement of Lipoprotein Lipase Activity

• Assay of the lipoprotein lipase activity in the plasma, after ten minutes of post Intravenous administration of heparin. Here the post heparin plasma is added to VLDL substrate and the liberated free fatty acids are assayed, and the lipoprotein lipase activity is expressed as micromoles of the released free fatty acids released per minute per liter of the plasma, that is, micromoles/l/min, after subtraction of hepatic lipase activity. Carriers of pathogenic mutations in either the lipoprotein lipase enzyme or its cofactor, that is, apolipoprotein C-II, will lead to undetectable lipoprotein lipase activity in the post heparin plasma which is a diagnostic of familial lipoprotein lipase deficiency.[27][28][26][28]
• Biopsies of the adipose tissue may also be used to determine the lipoprotein lipase activity directly.

Treatment / Management

Medical nutrition therapy involves following a fat-restricted diet to keep the individual diagnosed with lipoprotein lipase deficiency free of signs and symptoms. The targeted goal is to keep the plasma triglyceride levels below 2000 mg/dL, with the greatest benefit obtained when the plasma triglyceride levels are kept below 1000 mg/dL. This can be achieved by restricting the dietary fat intake to not above 20 g/day or 15% of total energy intake.

Fish oil supplements are not beneficial and are contraindicated in lipoprotein lipase deficiency, unlike the disorders of excess hepatic triglyceride production. This is because fish oils contribute to chylomicrons. Certain agents like alcohol, oral estrogens, beta-adrenergic blockers, diuretics, selective serotonin reuptake inhibitors, isotretinoin, are avoided as they are known to increase the endogenous triglyceride levels.[1][26] For individuals who take a very low-fat diet, it is recommended that they should supplement fat-soluble vitamins, that is, vitamin A, D, E, K, and minerals in their diet.

Acute pancreatitis associated with lipoprotein lipase deficiency is treated in the same manner as acute pancreatitis due to other causes. Prevention of recurrent acute pancreatitis helps to decrease the risk of secondary complications of pancreatitis like diabetes mellitus.

Plasma triglycerides are followed overtime of the affected individual as this helps to evaluate the success of the fat-restricted diet. 

Pregnant women need to follow an extreme fat-restricted diet, that is, less than 2 g/day, especially during the second and third trimesters. This, along which close monitoring of the plasma triglyceride levels, leads to the delivery of normal infants with normal plasma levels of essential fatty acids. A combination of a very low-fat diet with the use of gemfibrozil has been safely implicated in pregnancy.[1][29](B3)

For family planning, it is appropriate to offer genetic counseling to young adults who are affected, are carriers, or at risk of being a carrier.

Lipoprotein lipase (LPL) gene therapy, that is, alipogene tiparvovec gene therapy, consists of the LPL Ser447X variant in a genetically engineered adeno-associated virus genotype 1 (alipogene tiparvovec). The intramuscular administration of the adenovirus vector introduces a functional copy of the lipoprotein lipase gene into the patient's muscle cells, thus lowering the fasting triglyceride levels.[30][31][32] The maximum benefit is for individuals with the highest risk of complications. However, due to low demand from the patient community, it has been taken off the market.[1][33][34](B3)

Currently, there are some promising treatment approaches, that include the following:

• Pradigastat is a diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor that is orally administered. It functions by catalyzing the final step in triglyceride synthesis and decreases the chylomicron-triglyceride secretion.[23][35][23]
• Evinacumab is a monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3). It is an inhibitor of LPL and endothelial lipase.[23]

Differential Diagnosis

LPL deficiency is considered in young individuals with chylomicronemia and triglyceride levels of more than 2000 mg/dl. However, it has been found that such individuals do not necessarily have familial LPL deficiency. Instead, they may have one of the more common genetic disorders of triglyceride metabolism, like familial combined hyperlipidemia and monogenic familial hypertriglyceridemia, or there may be some secondary causes leading to hypertriglyceridemia.[1]

Other than LPL deficiency, that constitutes 95.0 percent of primary monogenic variants of chylomicronemia, the differential diagnoses for primary monogenic chylomicronemia include:

• Familial apolipoprotein C- II deficiency - severe chylomicronemia in childhood or adolescence, constitutes 2.0 percent of monogenic variants.
• Familial apolipoprotein A-V deficiency-chylomicronemia in late adulthood constitutes 0.6 percent of monogenic variants.
• Familial lipase maturation factor 1 deficiency- chylomicronemia in late adulthood, constitutes 0.4 percent of monogenic variants.
• Familial glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 deficiency-Chylomicronemia in late adulthood, constitutes 2.0 percent of monogenic variants.[1][36][37][38] 

The following secondary causes can also cause hypertriglyceridemia:

• Diabetes mellitus
• Paraproteinemia and lymphoproliferative disorders
• Alcohol use
• Estrogen therapy
• Drugs like selective serotonin receptor reuptake inhibitors, glucocorticoids, atypical antipsychotics, isotretinoin, certain antihypertensives[1]

Prognosis

Medical nutrition therapy is the mainstay for the treatment of lipoprotein lipase deficiency. Thus, treatment success depends on the acceptance of the fat-restricted diet of the individual affected. The ultimate prognosis of lipoprotein lipase deficiency appears to be good with high compliance for a fat-restricted diet that leads to a decrease in plasma triglyceride levels. The enlarged liver and spleen usually return to normal size within one week of lowering down of the plasma triglyceride levels, eruptive xanthomas clear within a few weeks to months.[1] In lipoprotein lipase deficiency, even with a history of recurrent attacks of acute pancreatitis, the pancreatic function declines slowly, so it is not associated with high mortality.[20][1]

Complications

In an individual with lipoprotein lipase deficiency, recurrent attacks of acute pancreatitis lead to chronic pancreatitis. The secondary complications of chronic pancreatitis are as follows:

• Diabetes mellitus
• Steatorrhea, that is, stools containing excess fat due to fat malabsorption
• Pancreatic calcifications

However, these complications are rare in an individual with lipoprotein lipase deficiency. Even if these complications occur, they are rare before mid-age. Pancreatitis might be rarely associated with serious complications like total pancreatic necrosis and death.[1]