Lipoprotein lipase deficiency is a genetic disorder with an autosomal recessive pattern of inheritance. It usually presents in childhood and is characterized by severe hypertriglyceridemia and chylomicronemia. It is the most common form of chylomicronemia and was formerly known as hyperlipoproteinemia type 1a. Lipoprotein lipase deficiency was first described by Dr. Burger and Dr. Grutz in 1932.
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.
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.
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. Males and females are affected equally.
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. Lipoprotein lipase is also required for maturation of small particles of high-density lipoproteins into larger particles.
Most of the mutations in the lipoprotein lipase gene are located on exons 2, 5, and 6. The well-known mutations include the following
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. 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.
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. However, the association of atherogenesis with lipoprotein lipase deficiency remains debated.
Lipoprotein lipase deficiency usually presents with the following:
Infants may present additionally with the following:
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.
The severity of the clinical presentation of lipoprotein lipase deficiency correlates with the chylomicron levels.
Lipoprotein lipase deficiency is suspected in young individuals with the following clinical findings in addition to the supportive laboratory findings.
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. Two test methods are used, which include:
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 :
Measurement of Lipoprotein Lipase Activity
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. 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.
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. 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.
Currently, there are some promising treatment approaches, that include the following:
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.
Other than LPL deficiency, that constitutes 95.0 percent of primary monogenic variants of chylomicronemia, the differential diagnoses for primary monogenic chylomicronemia include:
The following secondary causes can also cause hypertriglyceridemia:
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. 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.
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:
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.
The quality of life of the individuals affected with lipoprotein lipase deficiency is poor, mainly due to recurrent attacks of acute pancreatitis. Patients and their family members are noted to be anxious, depressed, and frustrated during and after hospitalizations for the attacks of pancreatitis. Recurrent hospitalizations affect various aspects of daily life, for example, work-life due to absenteeism, financial implications, and increased dependency on family and friends for support.
It is essential to educate the patient about the importance of following a strict fat-restricted diet to get relief from the signs and symptoms of lipoprotein lipase deficiency and to prevent its secondary manifestations. Daily life modifications, for example, using sources of medium-chain fatty acids for cooking, which get absorbed into the portal vein directly without getting incorporated into the chylomicron triglyceride, should be encouraged. A dietician consult could be helpful to achieve the goal of required daily fat consumption in the diet. Periodic follow-up for diet review along with the plasma triglyceride levels can help ensure therapy success.
Genetic counseling, that is, educating the affected individual about the nature, mode of inheritance, and the impact of this condition, is also quite important. This is because early diagnosis of this condition and early dietary modification helps the prevention of symptoms and medical complications to manifest. This will help the patient to make informed medical and personal decisions.
Though lipoprotein lipase deficiency is a rare genetic disorder, its implications on the life of an affected individual are quite debilitating. Most of it is attributed to the recurrent attacks of acute pancreatitis that leads to multiple hospitalizations. The manifestations of this disorder, the need to follow a strict fat-restricted diet and associated impaired psychosocial functioning have a poor impact on the Health-Related Quality of Life (HRQoL). The lack of proven effective and cost-effective therapies further increase the disease burden.
The unmet need for proper and consistent dietary advice, as well as the education of the patients and their friends and family, can be addressed by the following measures:
It is essential to consult with an interprofessional team of specialists that include a pediatrician, gastroenterologist, surgeon, endocrinologist, ophthalmologist, gynecologist, and a dietician. The nurses are also a vital member of the interprofessional group as they will monitor the patient's vital signs and assist with the education of the patient and family. The pharmacist will ensure that the patient is on the right analgesics in the event of attacks of acute pancreatitis. The radiologist also plays a vital role in determining the cause of abdominal pain. In cases where evidence is not definitive or minimal, expert opinion from the specialist may be utilized to recommend the type of diagnostic test or treatment. However, to improve outcomes, prompt consultation with an interprofessional group of specialists is recommended.
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