eMedicine Specialties > Endocrinology > Metabolic Disorders
Lecithin-Cholesterol Acyltransferase Deficiency
Updated: Jan 15, 2010
Introduction
Background
Lecithin-cholesterol acyltransferase (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
The 2 familial forms of LCAT deficiency are termed familial LCAT deficiency (complete LCAT deficiency) and fish eye disease (partial LCAT deficiency). 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.
Both familial LCAT deficiency and fish eye disease are autosomal recessive disorders caused by mutations of the LCAT gene. Because only one LCAT gene has been discovered, certain mutations of the LCAT gene result in familial LCAT deficiency, whereas other mutations of the gene cause fish eye disease.
Pathophysiology
The clinical manifestations of LCAT deficiency are probably due to a defect in LCAT-mediated cholesterol ester formation and, therefore, accumulation of unesterified cholesterol in certain tissues, such as the cornea, kidneys, and erythrocytes. Fish eye disease is characterized by partial reduction of LCAT and only manifests with progressive corneal opacification.
Frequency
International
Familial LCAT deficiency and fish eye disease are rare. More than 30 families, consisting of 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.
Mortality/Morbidity
- The major morbidity and mortality of familial LCAT deficiency is related to renal failure.1,2
- In fish eye disease, the major morbidity is corneal opacities causing visual impairment.
- These individuals have low HDL levels, but generally, premature atherosclerosis is uncommon. This may be due to the intact ability of plasma from persons with LCAT deficiency to remove cholesterol from cells as compared with plasma from healthy persons. However, several documented cases of premature atherosclerosis have been reported in patients with familial LCAT deficiency or fish eye disease.3,4,5
- Results from a study by Calabresi et al suggested 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.
Race
- A detailed analysis of ethnicity is difficult because of the rarity of this disease. Most of the reports are from western and northern Europe, but series have also been received from Japan, Algeria, and Australia.
Age
- Most patients are diagnosed during adulthood.
- Only a few cases have been diagnosed during the symptom-free teenage years.
Clinical
History
- 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 (~30% of cases). Family history also may be positive for similar manifestations.
Physical
- Familial LCAT deficiency
- Corneal opacities: The corneal 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.
- Anemia
- 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.
- Fish eye disease
- 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.
Causes
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.
More on Lecithin-Cholesterol Acyltransferase Deficiency |
 Overview: Lecithin-Cholesterol Acyltransferase Deficiency |
| Differential Diagnoses & Workup: Lecithin-Cholesterol Acyltransferase Deficiency |
| Treatment & Medication: Lecithin-Cholesterol Acyltransferase Deficiency |
| Follow-up: Lecithin-Cholesterol Acyltransferase Deficiency |
| References |
| Further Reading |
| Next Page » |
References
Moradi H, Pahl MV, Elahimehr R, et al. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl Res. Feb 2009;153(2):77-85. [Medline].
Vaziri ND. Causes of dysregulation of lipid metabolism in chronic renal failure. Semin Dial. Nov-Dec 2009;22(6):644-51. [Medline].
Rousset X, Vaisman B, Amar M, et al. Lecithin: cholesterol acyltransferase--from biochemistry to role in cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. Apr 2009;16(2):163-71. [Medline].
Calabresi L, Favari E, Moleri E, et al. Functional LCAT is not required for macrophage cholesterol efflux to human serum. Atherosclerosis. May 2009;204(1):141-6. [Medline].
Dullaart RP, Perton F, van der Klauw MM, et al. High plasma lecithin:cholesterol acyltransferase activity does not predict low incidence of cardiovascular events: possible attenuation of cardioprotection associated with high HDL cholesterol. Atherosclerosis. Jul 30 2009;[Medline].
Calabresi L, Baldassarre D, Castelnuovo S, et al. Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans. Circulation. Aug 18 2009;120(7):628-35. [Medline].
Bérard AM, Clerc M, Brewer B, Santamarina-Fojo S. A normal rate of cellular cholesterol removal can be mediated by plasma from a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency. Clin Chim Acta. Dec 2001;314(1-2):131-9. [Medline].
Elkhalil L, Majd Z, Bakir R, et al. Fish-eye disease: structural and in vivo metabolic abnormalities of high-density lipoproteins. Metabolism. May 1997;46(5):474-83. [Medline].
Hirano K, Kachi S, Ushida C, Naito M. Corneal and macular manifestations in a case of deficient lecithin: cholesterol acyltransferase. Jpn J Ophthalmol. Jan-Feb 2004;48(1):82-4. [Medline].
Kuivenhoven JA, Pritchard H, Hill J, et al. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res. Feb 1997;38(2):191-205. [Medline].
Mertens A, Verhamme P, Bielicki JK, et al. Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation. Apr 1 2003;107(12):1640-6. [Medline].
Pritchard PH, Hill JS. Genetic disorders of lecithin:cholesterol acyltransferase. In: Betterridge J, Illingworth R, Sheperd J, eds. Lipoproteins in Health and Disease. 799-814. ed. London, England: Hodder and Stoughton; 1999:799-814.
Santamarina-Fojo S, Hoef J, Assmann G. Lecithin: cholesterol acyltransferase deficiency and fish-eye disease. In: Wonsiewicz M, Noujaim S, Boyle P, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:2817-33.
Further Reading
Clinical guidelines:
Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. National Kidney Foundation - Disease Specific Society. 2003 Apr. 91 pages. NGC:003133
Screening and management of hyperlipidemia. Michigan Quality Improvement Consortium - Professional Association. 2003 Aug (revised 2007 Aug). 1 page. NGC:005979
Screening for lipid disorders in adults: U.S. Preventive Services Task Force recommendation statement. United States Preventive Services Task Force - Independent Expert Panel. 1996 (revised 2008 Jun). 13 pages. NGC:006542
Screening for lipid disorders in children. United States Preventive Services Task Force - Independent Expert Panel. 2007 Jul 9. 5 pages. NGC:005678
VA/DoD clinical practice guideline for the management of dyslipidemia. Department of Defense - Federal Government Agency [U.S.]
Department of Veterans Affairs - Federal Government Agency [U.S.]
Veterans Health Administration - Federal Government Agency [U.S.]. 2001 Dec (revised 2006). 140 pages. NGC:005303
Keywords
lecithin-cholesterol acyltransferase deficiency, LCAT, cholesterol synthesis, acyltransferase, high-density lipoprotein, HDL cholesterol, low-density lipoprotein, LDL cholesterol, fish-eye disease, fish eye disease, corneal opacities, hypoalphalipoproteinemia, corneal opacity
