Lecithin-Cholesterol Acyltransferase Deficiency

Background

Lecithin-cholesterol acyltransferase (LCAT) is a lipoprotein-associated enzyme which plays a large role in the esterification of free cholesterol, the maturation of high density-lipoprotein (HDL) particles, and the intravascular stage of reverse cholesterol transport (RCT). LCAT is an enzyme bound to HDLs and low-density lipoproteins (LDLs) in the plasma. LCAT catalyzes the formation of cholesterol esters in lipoproteins as follows:

unesterified cholesterol + phosphatidylcholine → cholesterol ester + lysophosphatidylcholine

The two familial forms of LCAT deficiency are termed familial LCAT deficiency (complete LCAT deficiency) and fish eye disease (partial LCAT deficiency). Familial LCAT deficiency (FLD), first reported in 1967 in a Norwegian family, is characterized by the absence of LCAT activity towards HDL and LDL. Fish eye disease, initially described in two families of Swedish origin, is characterized by the absence of LCAT activity towards HDL only.

Familial LCAT deficiency and fish eye disease are both autosomal recessive disorders caused by mutations of the LCAT gene. ^[1] Only one LCAT gene has been discovered, with certain mutations of the gene resulting in familial LCAT deficiency and other mutations of the gene causing fish eye disease. ^{[2, 3]} The exact location of the mutations of the LCAT gene cannot yet be used to predict the clinical or biochemical manifestations of either familial LCAT deficiency or fish eye disease.

The clinical manifestations of LCAT deficiency are likely due to a defect in LCAT-mediated cholesterol ester formation and, therefore, accumulation of unesterified (free) cholesterol in certain tissues, such as the cornea, kidneys, and erythrocytes. Patients may present with HDL deficiency, corneal opacification, hemolytic anemia, hypertension, hypertriglyceridemia, and proteinuria that typically progresses to end-stage renal disease (ESRD) by age 40–50 years; ESRD is the primary cause of morbidity and mortality. ^[1] LpX, an abnormal multivesicular-like lipoprotein that accumulates in patients with FLD, contributes to renal disease. ^[4] Fish eye disease is characterized by partial reduction of LCAT and only manifests as progressive corneal opacification.

Occurrence

Familial LCAT deficiency and fish eye disease are rare. Out of 70 families screened worldwide, at least 60 patients with either familial LCAT deficiency or fish eye disease have been reported. ^[5]

A detailed analysis of ethnicity in familial LCAT deficiency and fish eye disease is difficult because of the rarity of these conditions. Most of the reports are from western and northern Europe, but series have also been received from Japan, Algeria, and Australia.

Most patients are diagnosed during adulthood. Only a few cases have been diagnosed during the symptom-free teenage years.

Patient education

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History

The clinical and biochemical features of familial LCAT deficiency and fish eye disease are highly variable. In patients with familial LCAT deficiency, symptoms are related to anemia, corneal opacities, renal insufficiency, and atherosclerosis (rarely). Corneal opacities may be severe enough to require corneal transplantation for the restoration of vision. Family history may reveal similar clinical features in siblings.

In patients with fish eye disease, symptoms typically include corneal opacities and atherosclerosis (about 30% of cases). Family history also may be positive for similar manifestations.

Physical examination

Clinical manifestations of familial LCAT deficiency include the following:

• Corneal opacities

• Signs of renal insufficiency, including hypertension

• Signs of atherosclerosis in rare cases

• Xanthelasma (may be seen in end-stage disease)

• Hepatomegaly, splenomegaly, and lymphadenopathy - Generally, these are not present, despite the accumulation of lipid-laden foam cells.

The lesions of corneal manifestations consist of minute, grayish dots throughout the corneal stroma. The corneal opacities are more prominent in the periphery, develop in early childhood, and can be easily detected in the second decade of life. Papilledema with impaired ocular blood supply, leading to functional visual loss, has also been reported.

Clinical manifestations of fish eye disease include the following:

• Corneal opacities - The appearance of the corneas is similar to the eyes of a boiled fish; the degree of corneal opacification is more severe in persons with fish eye disease, resulting in visual impairment at an early age

• Signs of atherosclerosis (in rare cases)

• Hepatomegaly, splenomegaly, and lymphadenopathy - Generally, these are not present, despite the accumulation of lipid-laden foam cells

When patients present with unexplained low HDL levels, renal insufficiency, or corneal opacities, providers should keep LCAT deficiency as a differential diagnosis with clinical coordination.

Differential diagnosis

Conditions to consider in the differential diagnosis of familial LCAT deficiency and fish eye disease include the following:

• Apolipoprotein (apo)A-I/apoC-III/apoA-IV deficiency

• ApoA-I deficiency

• Combined apoA-I/apoC-III deficiency

• Familial dyslipidemia

• Familial hypoalphalipoproteinemia

• Tangier disease

• Familial hypercholesterolemia

• Polygenic hypercholesterolemia

• Hypertriglyceridemia

Lab studies

A definitive diagnosis of familial LCAT deficiency or fish eye disease requires mutational analysis of the LCAT gene and a functional analysis of the mutated gene product. However, numerous other lab studies can be used in the diagnosis of these diseases.

Lab findings in familial LCAT deficiency include the following:

• Complete blood count (CBC) - Normochromic normocytic anemia with anisopoikilocytosis, target cells, stomatocytes, and hematologic evidence of hemolysis may be present

• Urinalysis - Proteinuria is commonly detected during the second or third decade of life; less common findings include hyaline and granular casts and red blood cells.

• Progressive renal insufficiency - Occurs in some patients; laboratory evidence for progressive renal insufficiency includes increased plasma blood urea nitrogen (BUN), increased plasma creatinine, and decreased creatinine clearance

• Lipid Panel - Low HDL-C levels (generally < 10mg/dL), elevated very low-density lipoprotein (VLDL) and triglyceride levels, high concentrations of plasma unesterified cholesterol, low concentrations of plasma cholesterol ester

• Negligible plasma LCAT activity - Plasma fails to esterify radioactive cholesterol in exogenous apo A-I–containing liposomes.

• Negligible plasma cholesterol esterification rate - Plasma fails to esterify radioactive cholesterol in endogenous lipoproteins.

Lab findings in fish eye disease include the following:

• No anemia upon CBC count

• No proteinuria upon urinalysis

• No laboratory evidence of renal insufficiency

• Lipid Panel - Low HDL-C (10% of normal), elevated VLDL and triglyceride levels, elevated unesterified cholesterol in HDL, low cholesterol ester in HDL but normal in LDL and VLDL

• Negligible LCAT activity in HDL

• Normal plasma cholesterol esterification rate

• Failure of plasma to esterify radioactive cholesterol in exogenous lipoproteins or HDL, but not in LDL

Considerations in lab studies

Measurements of plasma LCAT activity ^[6] and the plasma cholesterol esterification rate and genetic testing for LCAT gene mutations are not routinely performed in most laboratories. Referrals to experts in lipoprotein research are often required to make a definitive diagnosis.

Histologic findings

Foam cells are found in biopsy specimens from the bone marrow, kidneys, and spleen. Sea-blue histiocytes by Giemsa staining are found in the bone marrow and spleen. Postmortem studies have shown atherosclerotic changes of the aorta and arteries in some patients with familial LCAT deficiency and fish eye disease.

Currently, no definitive therapy for LCAT deficiency exists. When indicated, symptomatic treatment is indicated for anemia, renal insufficiency, and atherosclerosis. Renal replacement by dialysis is necessary in patients who develop kidney failure.

Research on recombinant human LCAT (rLCAT) in renal disease is ongoing. ^[7] Studies have shown evidence of lipid profile normalization after rLCAT injections in mice and increased HDL in humans with coronary artery disease. ^{[8, 9]}

In a phase 1 study, 16 stable patients with coronary artery disease were injected with a single intravenous adminstration of recombinant LCAT (ACP-501) replacement therapy. Six hours after injection, those who received higher doses of ACP-501 were found to have increased HDL-C levels compared to their baseline HDL-C levels. The increased HDL levels though lasted for only up to 4 days. The administration of ACP-501 was safe and well tolerated by these patients. ^[9]

In a study of rhLCAT infusions in FLD, a single patient with advanced renal disease was infused with rhLCAT (ACP-501) over 1 hour on 3 occasions in a dose optimization phase (0.3, 3.0, and 9.0 mg/kg), then 3.0 or 9.0 mg/kg every 1–2 weeks for 7 months in a maintenance phase. LCAT concentration peaked at the end of each infusion and decreased to near baseline over 7 days. Renal function generally stabilized or improved and anemia improved. After infusion, HDL-C rapidly increased, peaking near normal in 8–12 hours; LDL-C increased more slowly than HDL-C. The researchers noted that rhLCAT infusions were well tolerated and the positive findings support continued development of rhLCAT therapy. ^[10]

Freeman and colleagues conducted a study to investigate the mechanism for LCAT activation by compound A and to determine whether it can also increase activity of some natural LCAT mutations. Results of the study showed that compound A can activate a subset of FLD mutations by forming a hydrophobic adduct with Cys31 near the active site. Functional groups in compound A responsible for LCAT activation were also identified, and a new class of LCAT activators based on sulfhydryl-reactive beta-lactams were described. These findings provide insights into LCAT activation that may be used to design novel LCAT activators. ^[11]

Short-term whole blood or plasma transfusion has been tried to replace the LCAT enzyme in some patients with familial LCAT deficiency, but it did not correct anemia, proteinuria, or lipoprotein abnormalities.

Transplantation

The following transplantation procedures may be indicated:

• Kidney transplantation - Indicated in patients with familial LCAT deficiency and renal failure

• Corneal transplantation - Indicated in patients with severely reduced vision due to corneal opacities

Consultations

Consultations with the following specialists may be beneficial:

• Endocrinologist - Consultation for diagnosis and dietary therapy to improve the abnormal lipid findings of hypertriglyceridemia and low HDL

• Ophthalmologist - Consultation to monitor visual acuity, presence of papilledema, and the need for interventions such as corneal transplantation

• Nephrologist - Consultation is useful in the staging and replacement of kidney function if the kidneys become compromised by LCAT deficiency

Outpatient care

In familial LCAT deficiency, renal function monitoring is imperative. This includes monitoring blood pressure, plasma BUN and creatinine values, 24-hour urinary protein levels, and creatinine clearance. Monitoring of visual acuity is also important since visual impairment due to corneal opacities may be progressive.

Additional treatment considerations

The following should also be kept in mind with regard to treatment ^[12] :

• Diet - Restriction of fat intake may be advisable in patients with familial LCAT deficiency, but no evidence supports its potential benefits

• Activity - Exercise, under the guidance of a physician, theoretically would have a role in the prevention of atherosclerosis in persons with LCAT deficiency

• Pharmacologic therapy - Because of the rarity of LCAT deficiency, pharmacologic therapy has not been specifically studied in a systematic fashion; however, case studies have reported benefit with statins and angiotensin receptor blockers in renal disease with LCAT. ^[13]

The major morbidity and mortality in familial LCAT deficiency is related to renal failure, with proteinuria manifesting in childhood and end-stage renal disease in adulthood, requiring renal replacement. ^{[14, 15]} In fish eye disease, the major morbidity is visual impairment from corneal opacities.

Although some documented cases of premature atherosclerosis have been reported in individuals with these diseases, premature atherosclerosis remains a controversial topic. ^{[16, 17, 18]} Ossoli et al reviewed several studies on the role of LCAT in atherosclerosis. They concluded that the available data is contradictory, but it clearly supported the concept that reduced plasma LCAT concentrations are not necessarily associated with increased atherosclerosis, despite the low HDL-C levels. They speculated that the preserved macrophage cholesterol removal associated with decreased LCAT function may be the reason why atherogenesis is not increased in these patients. ^[4]