Lecithin-Cholesterol Acyltransferase Deficiency

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](B3)

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.