Lecithin-Cholesterol Acyltransferase Deficiency 

The 2 familial forms of lecithin-cholesterol acyltransferase (LCAT) deficiency are termed familial LCAT deficiency (complete LCAT deficiency) and fish eye disease (partial LCAT deficiency). LCAT is an enzyme bound to high-density lipoproteins (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

Familial LCAT deficiency, 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 2 families of Swedish origin, is characterized by the absence of LCAT activity towards HDL only.

Familial LCAT deficiency and fish eye disease are autosomal recessive disorders caused by mutations of the LCAT gene. Only 1 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.^{[1, 2]}

The clinical manifestations of LCAT deficiency are probably 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. Fish eye disease is characterized by partial reduction of LCAT and only manifests as progressive corneal opacification.

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.

Occurrence

Familial LCAT deficiency and fish eye disease are rare. More than 30 families, together accounting for at least 60 patients, with familial LCAT deficiency have been reported worldwide. Approximately 20 patients with fish eye disease have been documented in the world literature.

Race- and age-related demographics

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.

Prognosis

Renal transplantation has been reported to be successful in some patients with familial LCAT deficiency, but it does not reverse the serum lipoprotein abnormalities or correct the anemia associated with this condition.

Familial LCAT deficiency and fish eye disease are associated with a modest increase in the risk for premature atherosclerosis.^{[3, 4, 5, 6]}

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

Patient Education

For patient education information, see the Cholesterol Center, as well as High Cholesterol, Cholesterol FAQs, and Lipitor (Atorvastatin).

The major morbidity and mortality of familial LCAT deficiency is related to renal failure.^{[7, 8]} In fish eye disease, the major morbidity is visual impairment from corneal opacities.

Patients with familial LCAT deficiency or fish eye disease have low HDL levels, but generally, although several documented cases of premature atherosclerosis have been reported in individuals with these diseases, premature atherosclerosis is uncommon in these patients.^{[3, 4, 5]} This may be due to the intact ability of plasma in persons with LCAT deficiency to remove cholesterol from cells, as compared with plasma from healthy persons.

Results from a study by Calabresi et al contradicted the notion that LCAT deficiency increases the risk for atherosclerosis, instead suggesting that neither familial LCAT nor fish eye disease promote the development of preclinical atherosclerosis.^[6] By measuring carotid intima-media thickness (IMT), the investigators assessed the extent of preclinical atherosclerosis in 40 individuals, from 13 Italian families, carrying LCAT gene mutations, with 80 healthy controls used for comparison.

The study's authors discovered that the average and maximum IMT values in the mutation group were actually lower (by 0.07 mm and 0.21 mm, respectively) than in the control group. The report also found a gene-dose dependence between inherited LCAT mutations and the reduction of carotid IMT. Moreover, persons with familial LCAT deficiency showed no significant difference in carotid IMT from individuals with fish eye disease.

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 characteristics of familial LCAT deficiency include the following:

• Corneal opacities
• Signs of renal insufficiency, including hypertension
• Signs of atherosclerosis in some 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.

With regard to corneal opacities, mentioned above, the lesions 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.

In fish eye disease, the physical examination includes evaluation for the following symptoms:

• Corneal opacities - Their appearance 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 some cases)
• Hepatomegaly, splenomegaly, and lymphadenopathy - Generally, these are not present, despite the accumulation of lipid-laden foam cells

Lab studies

A definitive diagnosis of familial LCAT deficiency or fish eye disease would require 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 - This occurs in some patients; laboratory evidence for progressive renal insufficiency includes increased plasma blood urea nitrogen (BUN), increased plasma creatinine, and decreased creatinine clearance
• Low concentrations of HDL cholesterol (generally < 10mg/dL)
• High concentrations of plasma unesterified cholesterol
• Low concentrations of plasma cholesterol ester
• Elevated very low-density lipoprotein (VLDL) and triglyceride levels
• 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
• Low concentrations (10% of normal) of HDL cholesterol
• High concentrations of unesterified cholesterol in HDL
• Low concentrations of cholesterol ester in HDL, but normal concentrations in LDL and VLDL
• Elevated VLDL and triglyceride levels
• 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 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.

Symptomatic treatment for anemia, renal insufficiency, and atherosclerosis is indicated. Renal replacement by dialysis is necessary in patients who develop kidney failure.

LCAT gene therapy or liver transplantation theoretically would be a treatment of choice to correct the underlying pathophysiology, but neither procedure has been reported.

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 - Schedule follow-up to monitor visual acuity, the 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, monitor renal function. This includes monitoring blood pressure, plasma BUN and creatinine values, 24-hour urinary protein levels, and creatinine clearance. Monitor visual acuity as well. Visual impairment due to corneal opacities may also be a concern in fish eye disease.

Additional treatment considerations

The following should also be kept in mind with regard to treatment:

• 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