Lecithin-Cholesterol Acyltransferase Deficiency
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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 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 two 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 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. 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. [1, 2] 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. Fish eye disease is characterized by partial reduction of LCAT and only manifests as progressive corneal opacification.
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. [18]
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.
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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.
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.
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
Polygenic hypercholesterolemia
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 – 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
Measurements of plasma LCAT activity [11] 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.
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. [16] Studies have shown evidence of lipid profile normalization after rLCAT injections in mice and increased HDL in humans with coronary artery disease. [14, 15] 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. [15]
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.
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 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
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.
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. [19]
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. [9, 10] 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. [3, 4, 5] 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. [17]
Shoji K, Morita H, Ishigaki Y, et al. Lecithin-cholesterol acyltransferase (LCAT) deficiency without mutations in the coding sequence: a case report and literature review. Clin Nephrol. 2011 Oct. 76(4):323-8. [Medline].
Holleboom AG, Kuivenhoven JA, Peelman F, et al. High prevalence of mutations in LCAT in patients with low HDL cholesterol levels in The Netherlands: identification and characterization of eight novel mutations. Hum Mutat. 2011 Nov. 32(11):1290-8. [Medline].
Rousset X, Vaisman B, Amar M, et al. Lecithin: cholesterol acyltransferase–from biochemistry to role in cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. 2009 Apr. 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. 2009 May. 204(1):141-6. [Medline].
Dullaart RP, Perton F, van der Klauw MM, Hillege HL, Sluiter WJ, PREVEND Study Group. High plasma lecithin:cholesterol acyltransferase activity does not predict low incidence of cardiovascular events: possible attenuation of cardioprotection associated with high HDL cholesterol. Atherosclerosis. 2010 Feb. 208(2):537-42. [Medline].
Calabresi L, Baldassarre D, Castelnuovo S, et al. Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans. Circulation. 2009 Aug 18. 120(7):628-35. [Medline].
Calabresi L, Simonelli S, Gomaraschi M, Franceschini G. Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease. Atherosclerosis. 2012 Jun. 222(2):299-306. [Medline].
van den Bogaard B, Holleboom AG, Duivenvoorden R, et al. Patients with low HDL-cholesterol caused by mutations in LCAT have increased arterial stiffness. Atherosclerosis. 2012 Dec. 225(2):481-5. [Medline].
Moradi H, Pahl MV, Elahimehr R, et al. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl Res. 2009 Feb. 153(2):77-85. [Medline].
Vaziri ND. Causes of dysregulation of lipid metabolism in chronic renal failure. Semin Dial. 2009 Nov-Dec. 22(6):644-51. [Medline].
Vaisman BL, Remaley AT. Measurement of lecithin-cholesterol acyltransferase activity with the use of a Peptide-proteoliposome substrate. Methods Mol Biol. 2013. 1027:343-52. [Medline].
Rader DJ, deGoma EM. Approach to the patient with extremely low HDL-cholesterol. J Clin Endocrinol Metab. 2012 Oct. 97(10):3399-407. [Medline]. [Full Text].
Rousset X, Vaisman B, Auerbach B, et al. Effect of recombinant human lecithin cholesterol acyltransferase infusion on lipoprotein metabolism in mice. J Pharmacol Exp Ther. 2010 Oct. 335(1):140-8. [Medline].
Shamburek RD, Bakker-Arkema R, Shamburek AM, e al. Safety and tolerability of ACP-501, a recombinant human lecithin:cholesterol acyltransferase, in a phase 1 single-dose escalation study. Circ Res. 2016 Jan 8. 118(1):73-82. [Medline].
van Capelleveen JC, Bewer HB, Kastelain JJ et al. Novel therapies focused on the high-density lipoprotein particle. Circ Res. 2014. 114:193-204.
Ossoli A, Simonelli S, Vitali C, Franceschini G, Calabresi L. Role of LCAT in Atherosclerosis. J Atheroscler Thromb. 2016. 23(2):119-27. [Medline].
Kunnen S, Van Eck M. Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?. J Lipid Res. 2012 Sep. 53(9):1783-99. [Medline].
Althaf MM, Almana H, Abdelfadiel A, Amer SM, Al-Hussain TO. Familial lecithin-cholesterol acyltransferase (LCAT) deficiency; a differential of proteinuria. J Nephropathol. 2015 Jan. 4(1):25-8. [Medline].
Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Attending Endocrinologist, Department of Medicine, Albert Einstein Medical Center
Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society
Disclosure: Nothing to disclose.
Linda Nguyen, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center
Linda Nguyen, MD is a member of the following medical societies: American College of Physicians, American Medical Association
Disclosure: Nothing to disclose.
George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society
Disclosure: Nothing to disclose.
Vasudevan A Raghavan, MBBS, MD MRCP(UK), Director, Cardiometabolic and Lipid (CAMEL) Clinic Services, Division of Endocrinology, Scott and White Hospital, Texas A&M Health Science Center College of Medicine
Vasudevan A Raghavan, MBBS, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Heart Association, Endocrine Society, Royal College of Physicians, National Lipid Association
Disclosure: Nothing to disclose.
Weerapan Khovidhunkit, MD, PhD Clinical Instructor, Department of Medicine, Division of Endocrinology and Metabolism, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thailand
Weerapan Khovidhunkit, MD, PhD, is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, and The Endocrine Society
Disclosure: Nothing to disclose.
David M Klachko, MBBCh Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri
David M Klachko, MBBCh, is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, Endocrine Society, Missouri State Medical Association, and Sigma Xi
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
Kent Wehmeier, MD Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD, is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
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Lecithin-Cholesterol Acyltransferase Deficiency
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