Lecithin-Cholesterol Acyltransferase Deficiency

Continuing Education Activity

Lecithin cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder in lipid metabolism, manifesting from early childhood through adulthood. Diminished HDL levels and the accumulation of cholesterol across various tissues characterize this condition. The condition exhibits 2 distinct clinical phenotypes, with complications such as renal dysfunction and corneal opacification contingent upon the specific phenotype. This activity reviews the characteristics of the disease, its underlying pathophysiology, and effective management strategies aimed at curtailing disease progression. Emphasis is placed on the critical need for timely identification of the disease and the proactive management of associated complications. The collaborative efforts of a comprehensive, interprofessional team are pivotal in optimizing patient care.

Clinicians participating in this activity can expect to gain a comprehensive understanding of this rare inherited syndrome. The focus includes insights into the pathology involving the partial or complete absence of LCAT enzyme activity, its impact on lipid metabolism, and the resulting abnormal lipid profiles. Participants will acquire knowledge crucial for diagnosing, managing, and mitigating complications related to impaired HDL metabolism.

Objectives:

• Differentiate between the clinical phenotypes associated with LCAT deficiency, understanding the distinct complications and manifestations of each phenotype.
• Identify the clinical and laboratory manifestations of LCAT deficiency.
• Implement evidence-based management strategies for LCAT deficiency, ensuring timely and effective interventions to mitigate disease progression and alleviate associated complications.
• Collaborate with healthcare professionals in various fields, fostering interdisciplinary teamwork to address the diverse aspects of LCAT deficiency, ensuring comprehensive patient care.

Introduction

Lecithin cholesterol acyltransferase (LCAT) deficiency is a rare inherited syndrome characterized by the partial or complete absence of LCAT enzyme activity.[1] LCAT is an enzyme attached to both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles and is responsible for the esterification of cholesterol, a crucial step in the metabolism of HDL particles. Deficiency of LCAT leads to impaired HDL metabolism, resulting in abnormal lipid profiles and predisposing to complications.[2] There are 2 clinical variants of the disease. The first is familial LCAT deficiency that involves a complete deficiency of the enzyme. The second is Fish-eye disease characterized by a partial deficiency of the enzyme.

Etiology

LCAT deficiency, an autosomal recessive disease, results from mutations in the LCAT gene located on chromosome 16 (16q22). The mutations result in either the complete deficiency of the functional LCAT enzyme (familial LCAT deficiency) or a partial reduction in the enzyme activity (Fish-eye disease).[3]

Epidemiology

LCAT deficiency is an extremely rare disorder, with only a few hundred cases reported worldwide. The exact prevalence of LCAT deficiency is unknown, but it is estimated to occur in approximately 1 in 1,000,000 individuals.[4] A detailed analysis of sex predilection and ethnicity is difficult, given the rarity of the condition.

Pathophysiology

Lipoproteins represent spherical complexes comprised of lipids encased by proteins and enveloped by a phospholipid monolayer. Metabolizing dietary triglycerides begins within the stomach and duodenum, where they are transformed into monoglycerides, free fatty acids, and unbound cholesterol. Bile acid micelles then move the molecules to the intestinal villi to be assimilated by enterocytes, reconverted into triglycerides, and repackaged as chylomicrons.[5]

These chylomicrons encounter metabolism through lipoprotein lipase, leading to the liberation of free fatty acids and monoglycerides. The remnants of chylomicrons, enriched with cholesterol, undertake transportation to the liver, where they undergo further metabolic processing to give rise to very low-density lipoprotein (VLDL). This VLDL is further degraded into lipoproteins abundant in cholesterol—intermediate density lipoprotein (IDL) and LDL.[6]

In contrast, HDL, devoid of cholesterol, emerges as particles synthesized within enterocytes and the liver. HDL assumes the role of acquiring cholesterol from peripheral tissues and other lipoproteins, subsequently facilitating its transportation to the liver and other bodily tissues. The process is mediated through the cholesterol ester transfer protein. Essential to the maturation and remodeling of HDL, the LCAT enzyme catalyzes the conversion of free cholesterol into cholesteryl esters within the HDL particles.[7]

In cases of LCAT deficiency, either impaired or absent LCAT activity, a consequential accumulation of free cholesterol within HDL particles transpires. As a result, the formation of cholesteryl esters becomes compromised, leading to the buildup of abnormal lipids, particularly unesterified cholesterol and phospholipids. This altered lipid composition significantly compromises the structural integrity and functional capacity of HDL particles.[8]

Histopathology

Documented studies reveal histological findings linked to LCAT deficiency. These findings include foam cells and sea-blue histiocytes observed in biopsies taken from bone marrow, spleen, and kidneys.[9][10]

History and Physical

The clinical presentation of the disease varies depending on the type of deficiency. Patients with familial LCAT deficiency exhibit a range of signs and symptoms, including corneal opacities, renal insufficiency, hemolytic anemia, atherosclerosis-related symptoms, xanthelasmata, hepatomegaly, splenomegaly, and lymphadenopathy.[11] The corneal opacities are minute, grayish dots dispersed across the corneal stroma, especially prominent at the corneal periphery.

In contrast, individuals with Fish-eye disease experience milder symptoms, often presenting with impaired vision due to corneal opacities. While this variant rarely showcases other symptoms seen in familial LCAT deficiency, splenomegaly, hepatomegaly, and lymphadenopathy may arise.[12] Notably, the Fish-eye variant often exhibits a more severe degree of corneal opacification.

Evaluation

Besides clinical observations and maintaining a high index of suspicion, laboratory findings remain pivotal in determining the diagnosis.

Individuals with complete LCAT deficiency often exhibit normochromic normocytic anemia, characterized by target cells and anisopoikilocytosis. Signs of hemolysis may manifest as heightened lactate dehydrogenase levels, indirect and direct hyperbilirubinemia, and diminished haptoglobin levels. Evaluating renal function is essential as patients are prone to progressive renal insufficiency with elevated blood urea nitrogen, plasma creatinine, proteinuria, and reduced creatinine clearance.[13]

The lipid panel is paramount. It highlights lipid abnormalities, such as markedly low HDL-C levels (usually <10 mg/dL), elevated VLDL and triglyceride levels, heightened plasma unesterified cholesterol concentrations, and reduced plasma cholesterol ester concentrations. The plasma LCAT enzyme activity measurement is typically indicative, with absence being the norm. The plasma fails to esterify radioactive cholesterol in exogenous apolipoprotein A-I containing liposomes. Currently, no test is available to assess the esterification of radioactive cholesterol within endogenous lipoproteins.

In contrast, Fish-eye disease exhibits distinct laboratory findings. It is characterized by low HDL-C levels (approximately 10% of normal), elevated VLDL and triglyceride levels, heightened unesterified cholesterol in HDL, and reduced cholesterol ester in HDL while remaining within the normal range for LDL and VLDL.[14] The rate of plasma cholesterol esterification is normal, although there is an incapacity of the plasma to esterify radioactive cholesterol in exogenous lipoproteins or HDL, except for LDL. There are no hematological or renal abnormalities

Routine measurement of LCAT activity is unavailable in most laboratories, necessitating referral to a specialized center for a definitive diagnosis.

Treatment / Management

There is no definitive treatment available for LCAT deficiency. Instead, the primary focus of management revolves around addressing its complications. This involves implementing dietary modifications, exercise, lipid-lowering therapies, and antihypertensive medications, particularly angiotensin-converting inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs). These measures constitute the cornerstone of treatment and have demonstrated efficacy in slowing disease progression. Additionally, corticosteroid therapy has been proposed as a potentially advantageous option.[15]

For individuals who develop end-stage renal disease (ESRD), options such as dialysis and renal transplantation are provided. While there is evidence of disease recurrence in renal allografts, it is important to note that acceptable long-term outcomes have been observed in transplant patients.

Looking towards the future, a potential therapeutic avenue involves recombinant human LCAT gene and enzyme replacement. In 1 study, the infusion of recombinant human LCAT enzyme exhibited improvements in anemia and renal function. Moreover, it led to transient normalization of lipid abnormalities.[16]

Differential Diagnosis

The conditions to consider in the differential diagnosis of LCAT deficiency include the following:

• Familial hypercholesterolemia: an autosomal dominant condition resulting in elevated LDL-C levels causing premature cardiovascular disease [17]
• Tangier Disease: autosomal recessive disorder and autosomal co-dominant patterns characterized by severe deficiency of HDL resulting in hyperplastic yellow or orange coloration of the tonsils, hepatosplenomegaly, and peripheral neuropathy [18]                                                                                       
• Niemann-Pick disease: an autosomal recessive lysosomal disorder characterized by accumulation of byproducts that leads to hepatosplenomegaly and cherry red spots [19]                                                              
• Hypertriglyceridemia: dyslipidemia due to elevated triglyceride levels resulting in acute pancreatitis, cardiovascular disease, and palmar xanthomas
• Familial HDL deficiency: an autosomal dominant disorder with low HDL and risk of premature cardiovascular events. The features of LCAT deficiency relating to corneal opacification and renal dysfunction typically are not present.[20]                                                                                                        
• Abetalipoproteinemia: rare autosomal recessive disorder resulting in low or absent cholesterol, LDL, and VLDL levels. Clinical features of this disease are red blood cell acanthocytes, fat malabsorption, spinocerebellar degeneration, and retinitis pigmentosa.[21]

Prognosis

The prognosis of LCAT deficiency hinges on the severity of the mutation. Complete LCAT deficiency manifests as a more severe disease that appears early in childhood, accompanied by pronounced symptoms. In contrast, partial LCAT deficiency with milder symptoms typically emerges later in life. Due to the condition's rarity, there is currently limited data on mortality rates.

Complications

The complications of LCAT deficiency vary depending on the subtype. In cases of complete LCAT deficiency, individuals often experience proteinuria, which indicates renal dysfunction.[22][23] This can eventually progress to renal failure, necessitating interventions like dialysis or a renal transplant.

On the other hand, those with partial LCAT deficiency commonly develop corneal opacification. This occurs due to the accumulation of cholesterol in the eyes, leading to significant visual impairment.

Both types of LCAT deficiency result in dyslipidemia due to the disruption of the regulatory role of HDL  in cholesterol transport. This disruption heightens the risk of atherosclerosis, which, in turn, increases the susceptibility to cardiovascular events such as myocardial infarction and stroke.

Consultations

Due to the intricate nature of this disease, an interdisciplinary approach is required for its optimal management. The consultations holding significant importance are the following:

• Endocrinologists and nutritionists can offer valuable insights into the diagnosis and dietary considerations.           
• Ophthalmologists play a crucial role in monitoring visual impairment and other eye-related complications. In some cases, more extensive interventions like a corneal transplant might be necessary.                                   
• Nephrologists are particularly valuable if renal impairment arises, as this could potentially necessitate dialysis.                                                                                                                                                                      
• Genetic counseling focuses discussions on the mode of inheritance, clinical manifestations, and potential complications.

Deterrence and Patient Education

HDL, also known as good cholesterol, is crucial in preventing significant cardiovascular events like heart attacks and strokes by extracting cholesterol from peripheral tissues and conveying it to the liver for metabolism. Moreover, HDL possesses unique attributes, including anti-inflammatory properties, endothelial function enhancement, and thrombus formation prevention.

Maintaining a healthy lifestyle is imperative through regular aerobic exercise, a balanced and nutritious diet, and smoking cessation. Specific dietary recommendations are advised for individuals with a heightened cardiovascular risk. Meals enriched with omega-3 fatty acids are particularly beneficial in such cases. A prime example of such a diet is the Mediterranean diet, characterized by its plant-based nature and abundance of healthy fats.

Enhancing Healthcare Team Outcomes

Managing LCAT deficiency requires a comprehensive, multidisciplinary approach involving experts from various fields, including endocrinology, nephrology, ophthalmology, and nutrition. Each specialist is pivotal in identifying complications and reducing the associated mortality and morbidity. This rare condition affects only a few individuals, so genetic counseling should be available following diagnosis. This counseling should cover essential topics such as the mode of inheritance, clinical manifestations, and potential complications. For individuals considering having children, prenatal testing can offer valuable insights.

Due to the rarity of this disease, there are currently no available randomized controlled trials. However, there is promising potential for therapy utilizing recombinant human LCAT enzyme, which has demonstrated beneficial effects.[24] Presently, the mainstay of management involves lifestyle adjustments and the use of antihypertensive medications, both of which have shown promise in slowing the progression of the disease.

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Disclosure: Jordan Carty declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.