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Lipoprotein Lipase Deficiency
Introduction
Lipoprotein lipase (LPL) deficiency is a genetic disorder inherited in an autosomal recessive pattern, typically presenting in childhood. This disorder is characterized by severe hypertriglyceridemia and chylomicronemia and is the most common form of chylomicronemia. Previously known as hyperlipoproteinemia type 1a,[1] the condition was first described by Drs Burger and Grutz in 1932.
Etiology
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Etiology
LPL deficiency arises from mutations in the LPL gene, leading to a significant reduction or complete loss of enzymatic activity. Pathogenic deletions, nonsense mutations, and splice-site variants lead to an abnormal LPL gene product, which results in an absent or truncated LPL enzyme that exhibits defective catalytic activity. More than 220 pathological variants have been identified, including 70% missense mutations, 18% nucleotide insertions and deletions, 10% nonsense mutations, and a few splice site variants.[2][3]
LPL mediates the lipolysis of plasma triglycerides in chylomicrons and other triglyceride-rich lipoproteins. The absence of LPL results in significant fasting and postprandial chylomicronemia, with triglyceride levels reaching 10 to 100 times above the normal range of 150 mg/dL (1.7 mmol/L).[4]
The most common form of familial chylomicronemia syndrome (FCS) is LPL deficiency, resulting from inactivating mutations in both alleles of the LPL gene. FCS can also result from mutations in other genes that encode proteins essential for LPL activity, including apolipoproteins C-II (APOC2) and A-5 (APOA5), glycosylphosphatidylinositol-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). Due to the recessive inheritance pattern, 2 heterozygous parents have a 25% chance of having a child affected by LPL deficiency and a 50% chance of having a heterozygous child with each pregnancy.[5][6]
Epidemiology
LPL deficiency is a rare disorder with an estimated prevalence of approximately 1 in 1,000,000 in the general population and a carrier frequency of about 1 in 500. In Quebec, Canada, 2 mutations—LPL p.118G>E and p.207P>L—have been identified as causing a complete loss of LPL activity in homozygotes and a 50% loss in heterozygotes. Most cases of LPL deficiency are diagnosed in childhood, typically before age 10, and 25 % of affected patients are identified during the first year of life. However, some individuals may not develop symptoms until adulthood, and females may present for the first time during pregnancy.[1][7] Both males and females are equally affected.
Pathophysiology
The LPL gene is located on human chromosome 8p21.3 and consists of 10 exons. The LPL enzyme, comprising 475 amino acids, is predominantly expressed in adipose tissue, cardiac muscle, and skeletal muscle. This enzyme is crucial in the hydrolysis of triglyceride-rich lipoproteins, primarily chylomicrons and very low-density lipoproteins (VLDL). The catalytic center of the enzyme harbors 3 amino acids—S132, D156, and H241.
LPL activity is regulated by various factors, including hormones, nonesterified fatty acids, and apolipoproteins. Apolipoprotein A-V (apoAV), apolipoprotein C-II (apoC-II), insulin, and acylation-stimulating proteins enhance LPL activity, whereas apoC-III and tumor necrosis factor-alpha (TNF-α) inhibit it. After LPL is produced in adipose tissues and muscles, which are the 2 primary production sites, it is secreted and transported to the luminal surface of capillary endothelial cells in extrahepatic tissues. Dietary fats absorbed in the intestines are transported as triglycerides within large lipoproteins called chylomicrons. Once chylomicrons are released into the bloodstream, they acquire a lipoprotein called apoC-II from HDL.
ApoC-II acts as a cofactor for LPL; its recognition activates the enzyme, leading to the breakdown of chylomicrons and VLDL triglycerides into nonesterified free fatty acids and 2-monoacylglycerol. These products are either stored as triglycerides in adipose tissue or used as an energy source in muscles.[8][9] Additionally, LPL is essential for the maturation of small HDL particles into larger ones.[10]
Most deleterious variants of the LPL gene are located in exons 2, 5, and 6. The notable deleterious variants include:
- c.1127A>T, resulting in p.291N>S in exon 6, is the most common LPL variant in White populations, found in 2% to 5% of heterozygous individuals. This variant is also associated with an increased risk of Alzheimer disease.[11]
- c.93T>G, located in the promoter region, has a G allele that is most prevalent in the Black population of South Africa (76.4%). The T allele appears at a rate of 1.7% in White populations.[12]
- p.D9N, located in exon 2, is a less common variant found in 1.6% to 4.4% of the population. Homozygous individuals for this variant exhibit a 20% reduction in LPL activity.[13]
- c.644G>A, located in exon 5, was previously documented as p.188G>E and is currently updated to p.215G>E. This occurs in 0.06% of the population.[14] This single nucleotide variant (SNV) is most frequently associated with homozygous chylomicronemia, particularly among French Canadians in Quebec. Additionally, this SNV is strongly linked to an increased risk of coronary artery disease.[14]
- A221-del (c.916delG), located in exon 5, results in homozygous chylomicronemia, and it is the most common mutation identified in the Japanese population. This mutation is also referred to as LPL Arita.[15]
- Carriers of the p.291N>S mutation or the combined mutation p.9D>N/93T>G are known to have an increased risk of preeclampsia.[16]
- S447X, now known to be located at position 474 in exon 9, is a gain-of-function mutation that increases LPL activity. This nonsense mutation is associated with a 0.8-fold reduced risk of ischemic heart disease, with the greatest benefit seen in individuals using beta-blockers.[17] Carriers of this mutation exhibit lower plasma triglyceride levels, higher HDL levels, and a lower incidence of cardiovascular disease compared to noncarriers.[18]
A reduction or complete loss of LPL activity prevents the breakdown of triglycerides, causing triglyceride accumulation in the blood and tissues. This accumulation leads to the clinical manifestations of LPL deficiency.[1] In homozygous individuals, serum triglyceride levels may exceed 10,000 mg/dL, whereas in heterozygous individuals, serum triglyceride levels typically range from 200 to 750 mg/dL.
Research suggests that a defect in lipolysis can be a risk factor for premature atherosclerosis. These studies were based on other metabolic disturbances, such as increased serum triglycerides and low HDLs. Additionally, postprandial triglyceride clearance is delayed, resulting in prolonged exposure to lipoproteins and increased oxidative damage. Even reverse cholesterol transport is impaired, as structural changes in HDL lead to faster and increased clearance of these particles.[10][19] Thus, the lipoprotein lipoprotein profile of patients with LPL deficiency resembles the postprandial profile, characterized by the production of atherogenic particles that may predispose individuals to atherosclerosis.[20] However, the direct association between LPL deficiency and atherogenesis remains a topic of debate.
History and Physical
LPL deficiency usually presents with a range of symptoms and signs associated with elevated lipid levels. Abdominal pain, the most common presenting symptom, often results from acute pancreatitis. The pain can range in intensity from mild discomfort to severe, incapacitating episodes resembling an acute abdomen. Recurrent episodes of acute pancreatitis frequently progress to chronic pancreatitis over time.[21]
Although the mechanism of acute pancreatitis following hypertriglyceridemia in patients with LPL deficiency is not fully understood, oral antioxidants have been shown to reduce the frequency of pancreatitis episodes, suggesting that oxidant damage may have a role.[22][23] The risk of acute pancreatitis is approximately 5% when serum triglyceride levels reach 1000 mg/dL or higher and 10% to 20% when levels exceed 2000 mg/dL.[24][25]
Approximately 50% of individuals with LPL deficiency develop eruptive xanthomas, which are yellow papules, typically around 1 mm in size. These lesions most commonly appear on the trunk, knees, buttocks, and extensor surfaces of the arms and may coalesce into larger patches. Xanthoma formation occurs due to the extravascular phagocytosis of chylomicrons by macrophages, leading to deposition in the skin. These lesions usually occur when plasma triglyceride levels exceed 2000 mg/dL and resolve when triglyceride levels return to normal. The lesions are generally painless unless subjected to repetitive abrasion.[1]
Loss of appetite, nausea, and vomiting are common symptoms reported by patients with LPL deficiency. Hepatosplenomegaly occurs due to significantly elevated plasma triglyceride levels. Excessive chylomicrons in the bloodstream are ingested by macrophages, which then travel to the liver and spleen. The accumulation of fatty cells in the liver and spleen leads to their enlargement.[1]
Arthralgias and myalgias are commonly reported symptoms, although the mechanism behind these complaints is not fully understood.
Lipemia retinalis is when retinal arterioles, venules, and the fundus appear pale pink due to scattering of light by the large chylomicrons. This change is reversible, and vision is typically spared. Lipemia retinalis is observed when plasma triglyceride levels exceed 2500 mg/dL. The peripheral retinal vessels appear thin when triglyceride levels range between 2500 and 3499 mg/dL. At levels between 3500 and 5000 mg/dL, the retinal vessels in the posterior pole take on a creamy color. When triglyceride levels exceed 5000 mg/dL, the retina appears salmon-colored, with the retinal venules and arteries displaying a creamy appearance.[26][27]
Neuropsychiatric changes, such as mild cognitive dysfunction, depression, and memory loss, have been reported. These changes are typically reversible.[8][28]
Infants with LPL deficiency may present additional symptoms, including pallor, seizures, and irritability. Abdominal symptoms can include pain (often resembling colic), diarrhea, gastrointestinal bleeding, and failure to thrive.[26]
In women, the presentation of LPL deficiency may be delayed until pregnancy, when significant signs and symptoms can occur. This is due to increased uptake of triglyceride-rich lipoproteins by macrophages, driven by elevated circulating apolipoprotein E (apoE) levels during pregnancy.[7] The severity of the clinical presentation of LPL deficiency correlates with the chylomicron levels.
Evaluation
LPL deficiency should be suspected in young individuals presenting with clinical findings described in the History and Physical section, supported by characteristic laboratory results.
Laboratory Evaluation and Pertinent Findings
- Milky-appearing plasma: This is caused by the impaired clearance of plasma chylomicrons.
- Plasma triglyceride levels: The levels exceed 2000 mg/dL regardless of the patient’s fasting state.
Diagnosis
The diagnosis of LPL deficiency is confirmed through molecular genetic testing, which detects biallelic pathogenic variants in the LPL gene.[29]
The 2 primary testing methods used include:
- Sequence analysis: This identifies biallelic pathogenic variants in 97% of probands.
- Gene-targeted duplication or deletion analysis: This identifies biallelic pathogenic variants in 4% of probands.
Molecular genetic testing can be performed on the LPL gene or to identify other genetic variants that may lead to chylomicronemia. Single-gene testing analyzes the LPL gene, and if one or no pathogenic variant is found, gene-targeted duplication or deletion analysis should be conducted. A multigene panel assesses the LPL gene along with genes associated with apoC-II, apoAV, LMF1, and GPIHBP1.[1][29]
Measurement of Lipoprotein Lipase Activity
Biopsies of adipose tissue may be used to directly determine the LPL activity; however, the recommended initial test is an assay of plasma LPL activity. Heparin is administered intravenously to perform this assay. The post-heparin plasma, obtained 10 minutes after heparin administration, is added to a VLDL substrate, and the liberated free fatty acids are measured.
LPL activity is expressed in μmol/L/min, reflecting the amount of free fatty acids released per liter of plasma per minute after subtracting hepatic lipase activity. Pathogenic variants in the lipase enzyme or its cofactor, apoC-II, result in undetectable lipoprotein lipase activity in post-heparin plasma, confirming a diagnosis of familial LPL deficiency.[29][30][31]
Treatment / Management
Medical nutrition therapy is the cornerstone of managing LPL deficiency, focusing on a fat-restricted diet to prevent the onset of signs and symptoms and complications. The primary goal is maintaining plasma triglyceride levels below 2000 mg/dL, with optimal outcomes observed when levels are kept below 1000 mg/dL. Achieving this target typically involves limiting dietary fat intake to less than 20 g/d or 15% of total energy intake.[32](A1)
Adherence to a fat-restricted diet significantly improves the clinical manifestations of primary chylomicronemia, including the resolution of hepatosplenomegaly, abdominal pain, and xanthomas, while also significantly reducing the risk of pancreatitis. However, maintaining this diet is challenging, and long-term compliance—particularly among young patients—tends to be poor. Support from a dietitian or nutritionist is highly recommended to help patients achieve and sustain the necessary low-fat intake targets.[33]
Managing lifestyle factors and addressing secondary causes of hypertriglyceridemia are crucial for patients with chylomicronemia. Key measures include avoiding alcohol, maintaining a healthy weight, and discontinuing medications known to exacerbate hypertriglyceridemia. Additionally, optimizing the management of conditions such as hypothyroidism, diabetes, and complications of nephrotic syndrome is essential for effective control.[32][34](A1)
Fish oil supplements are contraindicated for patients with LPL deficiency, as they promote chylomicron formation, unlike their beneficial effects in disorders characterized by excess hepatic triglyceride production. Agents such as alcohol, oral estrogens, older beta blockers, thiazide diuretics, selective serotonin reuptake inhibitors (SSRIs), and isotretinoin should be avoided, as they are known to elevate endogenous triglyceride levels.[1][29] For individuals on a very low-fat diet, dietary supplementation with fat-soluble vitamins (A, D, E, and K) and essential minerals is recommended to prevent deficiencies.
Acute pancreatitis associated with LPL deficiency is treated similarly to pancreatitis from other causes. Preventing recurrent episodes reduces the risk of secondary complications, such as diabetes. Regular monitoring of plasma triglyceride levels helps assess the effectiveness of a fat-restricted diet.
Traditional lipid-lowering medications, such as fibrates, niacin, and statins, used for mild-to-moderate hypertriglyceridemia, have minimal effectiveness in patients with primary chylomicronemia. However, anecdotal evidence indicates that these medications may benefit individuals without complete loss-of-function mutations in lipolytic pathway components or those with concomitant secondary factors contributing to hypertriglyceridemia.[32][35] (A1)
Pregnant patients with LPL deficiency must adhere to a very fat-restricted diet, limiting fat intake to less than 10% of total caloric consumption, particularly during the second and third trimesters. Some pregnant patients who experience epigastric or abdominal pain have been successfully treated with near-zero fat diets. This approach, along with close monitoring of plasma triglyceride levels, helps ensure the delivery of healthy infants with normal plasma levels of essential fatty acids. Additionally, a combination of a very low-fat diet and gemfibrozil has been used safely during pregnancy.[1][36] (B3)
Acute pancreatitis during pregnancy poses a life-threatening risk to both the mother and fetus, with an estimated incidence of 1 in 1,000 to 1 in 10,000 pregnancies. Gallstones are the most common cause of acute pancreatitis in pregnancy, followed by hypertriglyceridemia.[37] For family planning, genetic counseling should be offered to young adults who are affected, known carriers of deleterious variants, or at risk of being carriers.
Novel Treatments
Recent human genetic research has identified several novel targets for lipid-lowering therapy, including apoC-III, angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4, respectively), apolipoprotein V, and ATP citrate lyase. These targets hold the potential for improving outcomes in LPL deficiency and related atherosclerosis. ANGPTL3 is particularly notable, as it inhibits LPL activity, and monoclonal antibodies have been developed to target this protein.
Beyond the statin target approach for low-density lipoprotein (LDL), new treatments targeting triglyceride-rich lipoproteins have emerged and are advancing through clinical development. Biological and RNA-based agents now complement traditional small-molecule treatments, which have seen significant refinement. Innovative targeting strategies have enhanced the efficacy of these novel interventions while substantially improving their tolerability.[38][39](B3)
The development of antisense RNA and small interfering RNA technologies enables the selective inhibition of specific protein production. These advancements have paved the way for innovative therapeutic strategies targeting hepatocytes, which are the central cells involved in lipid metabolism. These therapies engage a hepatocyte-specific receptor by conjugating RNA therapeutics to a carbohydrate ligand containing a terminal N-acetyl galactosamine (GalNAc) residue, facilitating precise drug delivery to liver cells. This targeted approach significantly reduces the required dose of inhibitory RNAs and minimizes adverse effects, such as serious injection-site reactions, which were common with earlier RNA therapeutics. Some of these treatments are currently in Phase 3 trials.[40][41]
Currently, several promising treatment approaches are under development, including:
- Pradigastat: This is an orally administered diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor. This drug reduces chylomicron-triglyceride secretion by catalyzing the final step in triglyceride synthesis.[26][42]
- Evinacumab: This is a monoclonal antibody targeting ANGPTL3—an inhibitor of LPL and endothelial lipase.[26][38]
- Volanesorsen: This is an antisense oligonucleotide targeting apoC-III, a complementary DNA strand to the apoC-III mRNA transcript. This binding leads to the degradation of apoC-III mRNA and a reduction in apoC-III protein levels. ApoC-III inhibits LPL, increases VLDL production, decreases VLDL degradation, reduces hepatic lipase activity, and impairs receptor-mediated triglyceride clearance by the liver.[43][44]
Evinacumab is a monoclonal antibody that neutralizes ANGPTL3.[41][45] In 2021, the drug was approved by the US Food and Drug Administration (FDA) as an add-on treatment for adult and pediatric patients aged 12 and older with homozygous familial hypercholesterolemia. Evinacumab has also been tested in patients with refractory hypercholesterolemia from other causes, including LPL deficiency.[46] Evinacumab has been shown to significantly decrease triglycerides and LDL levels.[39][47] Another long-term study of patients with refractory hypercholesterolemia found a mean LDL reduction of 46% from baseline after 6 years. Adverse effects were common, including nasopharyngitis, elevated liver function tests, and diarrhea; however, none led to treatment discontinuation.[48](A1)
Volanesorsen was developed to treat FCS, of which LPL deficiency is one type. In patients with hyperchylomicronemia, volanesorsen reduced triglycerides by over 70%, although it caused injection-site reactions in nearly a quarter of patients.[49] The FDA did not approve volanesorsen due to concerns about safety and tolerability. However, it is approved in Europe for patients with genetically confirmed FCS based on the APPROACH and COMPASS trials.[47][50] Volanesorsen has also been used in case reports to treat LPL deficiency.[51](A1)
Fibrates can raise HDL and lower triglycerides by stimulating peroxisome proliferator-activated receptor-alpha (PPARα). A novel selective PPARα modulator, pemafibrate, effectively lowers triglycerides and apoC-III. Unlike older fibrates, which have limited PPARα activation due to their nonselectivity, pemafibrate is 2500 times more potent than fenofibrate in activating PPARα activation.[47] The large-scale PROMINENT trial demonstrated significant reductions in triglycerides, VLDL, remnant cholesterol, and apoC-III, although it did not improve cardiac outcomes, which was the trial's primary end point.[47][52][53](B3)
Alipogene tiparvovec is an LPL gene therapy approved in Europe, consisting of the LPL S447X variant delivered via a genetically engineered adeno-associated virus genotype-1. The intramuscular administration of the adenovirus vector introduces a functional copy of the LPL gene into the patient's muscle cells, thereby lowering fasting triglyceride levels. Despite significantly reducing triglycerides, this therapy is not widely available due to the development of anti-adenovirus antibodies with long-term use, which decreases its effectiveness. Additionally, there are concerns regarding its potential tumorigenic effects.[47][54][55][56](B3)
Several studies have demonstrated the benefits of nutraceuticals, including artichoke leaf extract, berberine, and bergamot. In a study involving over 700 patients, artichoke leaf extract resulted in a significant decrease in triglyceride levels, which is believed to be due to its effects on multiple liver pathways.[47](B3)
Differential Diagnosis
LPL deficiency is considered in young individuals with chylomicronemia and triglyceride levels exceeding 2000 mg/dL. However, these individuals may not necessarily have familial LPL deficiency. Instead, they could have more common genetic disorders of triglyceride metabolism, such as familial combined hyperlipidemia, monogenic familial hypertriglyceridemia, or secondary causes of hypertriglyceridemia.[1]
LPL deficiency accounts for 95% of primary monogenic variants of chylomicronemia. The differential diagnoses for other primary monogenic chylomicronemia include:
- Familial apoC-II deficiency: Severe chylomicronemia presenting in childhood or adolescence; constitutes 2.0% of monogenic variants.
- Familial apoAV deficiency: Chylomicronemia presenting in late adulthood; constitutes 0.6% of monogenic variants.
- Familial LMF1 deficiency: Chylomicronemia presenting in late adulthood; constitutes 0.4% of monogenic variants.
- Familial GPIHBP1 deficiency: Chylomicronemia in late adulthood; constitutes 2% of monogenic variants.[1][57][58][59]
The following secondary causes can also cause hypertriglyceridemia:
- Diabetes
- Paraproteinemia and lymphoproliferative disorders
- Alcohol use
- Estrogen therapy
- Medications, including SSRIs, glucocorticoids, atypical antipsychotics, isotretinoin, and certain antihypertensive drugs.[1]
Prognosis
Medical nutrition therapy is the cornerstone of treatment for LPL deficiency. The success of treatment largely depends on the individual's adherence to a fat-restricted diet. The ultimate prognosis of LPL deficiency is generally favorable with high compliance to a fat-restricted diet, which leads to a reduction in plasma triglyceride levels. The enlarged liver and spleen typically return to normal size within 1 week of lowering plasma triglyceride levels, and eruptive xanthomas usually clear within a few weeks to months.[1] In LPL deficiency, despite a history of recurrent acute pancreatitis attacks, pancreatic function declines slowly, and the condition is not associated with high mortality.[23]
Complications
In individuals with LPL deficiency, recurrent acute pancreatitis can lead to chronic pancreatitis. The secondary complications of chronic pancreatitis include diabetes, steatorrhea, and pancreatic calcifications. However, these complications are rare in individuals with LPL deficiency and typically do not occur before middle age. In rare cases, pancreatitis may be associated with serious complications such as total pancreatic necrosis and death.[1]
Deterrence and Patient Education
The quality of life for individuals with LPL deficiency is often poor, primarily due to recurrent acute pancreatitis attacks. Patients and their families frequently experience anxiety, depression, and frustration during and after hospitalizations for these episodes. Recurrent hospitalizations affect various aspects of daily life, including work-life due to absenteeism, financial implications, and increased dependency on family and friends for support.[60][61]
Educating patients on the importance of following a strict fat-restricted diet is essential for alleviating the signs and symptoms of LPL deficiency and preventing its secondary complications. Lifestyle modifications, such as using sources of medium-chain fatty acids for cooking (which are absorbed directly into the portal vein without being incorporated into chylomicron triglycerides), should be encouraged. A consultation with a dietitian can help achieve the necessary daily fat intake. Regular follow-up, including diet reviews and monitoring plasma triglyceride levels, is essential to ensure the success of the therapy.[1]
Genetic counseling, which involves educating the affected individual about the nature, mode of inheritance, and impact of the condition, is crucial. Early diagnosis and dietary modification can prevent the onset of symptoms and medical complications.[58] This enables the patient to make informed medical and personal decisions.
Enhancing Healthcare Team Outcomes
Although LPL deficiency is a rare genetic disorder, its implications on the affected individual's life can be debilitating, primarily due to recurrent attacks of acute pancreatitis leading to multiple hospitalizations. The manifestations of this disorder, the need for a strict fat-restricted diet, and the associated psychosocial challenges negatively affect health-related quality of life. The absence of proven, effective, and cost-efficient therapies further exacerbates the disease burden.
The unmet need for consistent dietary guidance and education for patients and their families can be addressed through the following measures:
- Healthcare professionals should acquire comprehensive knowledge of the disorder to provide appropriate dietary recommendations during hospitalizations and help patients understand their condition, enabling them to adhere to a strict diet at home.
- Emotional support services and support groups can help alleviate the uncertainty and fear associated with future acute pancreatitis attacks.
- Providing materials with reliable information about the disorder can help alleviate the anxiety and stress experienced by patients and their families.
Consulting an interprofessional healthcare team of specialists, including a pediatrician, gastroenterologist, surgeon, endocrinologist, ophthalmologist, gynecologist, and dietitian, is essential for comprehensive care. Nurses are crucial in monitoring the patient's vital signs and assisting with patient and caregiver education. Pharmacists ensure appropriate analgesics during acute pancreatitis episodes and review potential medication interactions. Radiologists contribute by interpreting necessary imaging studies. Input from specialists can guide the selection of diagnostic tests and treatments. To optimize outcomes, timely consultation with this diverse team is highly recommended.
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