Lecithin cholesterol acyltransferase deficiency

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Lipid Disorders Main Page

Overview

Causes

Classification

Abetalipoproteinemia
Hypobetalipoproteinemia
Familial hypoalphalipoproteinemia
LCAT Deficiency
Chylomicron retention disease
Tangier disease
Familial combined hypolipidemia

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: LCAT deficiency, dyslipoproteinemic corneal dystrophy, fish eye disease, Norum disease, partial LCAT deficiency

Overview

Lecithin cholesterol acyltransferase(LCAT) is the enzyme responsible for esterification of free cholesterol. LCAT deficiency is a monogenic autosomal rescessive disease, with a mutation in the LCAT gene on chromosome number 16. Patients with homozygous and compound heterozygous mutations are affected and have an accumulation of free cholesterol in the cornea, RBC membrane, and kidney, resulting in symptoms. The disease is classified, by the presentation and location, into complete enzyme deficiency(Familial LCAT deficiency) and incomplete enzyme deficiency(Fish Eye Disease). The characteristic findings in patients with LCAT deficiency include have low HDL C levels.

Historical Perspective

  • In 1962, Glomset identified an enzyme (plasma fatty acid transferase) which transfers fatty acid onto free cholesterol that creates a cholesterol ester.
    • This helps in the formation of a mature HDL particle, which is a crucial step in reverse cholesterol transport [1].
  • In 1967, Norum and Gjone described a disease for the first time in a patient from Norway with features of normochromic anemia, proteinuria and corneal lipid deposits[2].
  • In 1967, Norum and Gjone reported that two sisters of the affected patient had similar presentation along with low levels of cholesterol esters and lysolecithin in the serum, with increased total body cholesterol, triglyceride and phospholipid.
  • In 1986, McLean and colleagues reported the complete gene sequence and sites expression of lecithin cholesterol acyl transferase gene (LCAT). The location of the gene is identified to be on q21-22 region of chromosome 16 [4] and is synthesized mainly in the liver.

Demographics, Natural History and Complications

  • If left untreated patient will develop progressive decline in renal function to end stage renal disease.
  • Low HDL is a risk factor for development of cardiovascular disease[5], but the role of LCAT in atherosclerosis is still not well defined and is controversial[6][7].

Pathophysiology

Pathogenesis

LCAT Function

  • Majority of the enzyme is associated with HDL C, very small amount with LDL C[8].
 
 
 
LCAT synthesized in liver and released into circulation and is picked up by HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apo A1 activates LCAT on HDL, Apo E activates LCAT associated with LDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LCAT cleaves fatty acid from phosphotidylcholine
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfers fatty acid to beta hydroxyl group of free cholesterol(FC) taken up by HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Results in the formation of cholesterol esters which help in maturation of HDL C and also forms lysophosphotidylcholine
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Esterification of FC taken up by HDL C, is α-LCAT activity. Esterification of FC associated with Apo B ( LDL C), is β-LCAT activity. This differntiation into alpha and beta is based on the HDL and LDL mobility on electrophoresis[9]
 
 
 
  • LCAT helps in reverse cholesterol transport by:[10]
    • Cholesterol esters due to the hydrophobic nature occupy the core of the lipoprotien, which prevent the backflow of cholesterol into the cells.
    • LCAT promotes unidirectional efflux of free cholesterol from the cells via ABCA1 and scavenger receptor type B-I (SR-BI) by creating a concentration gradient.

LCAT Deficiency

 
 
 
Loss of LCAT function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Loss of alpha function leads to failure HDL maturation resulting in elevated FC, phospholipids, Apo E and pre beta HDL and low Apo A1 and Apo A2 levels
 
 
 
Loss of beta function results in elevated FC, phospholipids and formation of cholesterol rich multilamellar particle called Lipoprotien X [11], which are implicated in the development of glomerulopathy[12] [13].

Genetics

  • Autosomal Recessive inheritance, monogenic disorder.
  • LCAT gene is on chromosome 16, multiple mutation sites are identified.[14]
  • Expression of clinical features and severity of disease in homozygous patients depends on the type and locus of the mutation[15].
  • Heterozygous patients have a intermediate biochemical expression with reduced plasma HLD-C and apoA-I levels[7] .

Microscopy

  • Cornea and RBC membrane show deposition of excess cholesterol and phospholipids resulting in the corneal opacities and hemolysis respectively.
  • Kidney biopsy in the early stage of the disease show mild mesangium enlargement and thickening of glomerular basement membrane (GBM). Lipid filled foamy deposits are seen in the glomerular basement membrane. Lipid analysis of isolated glomeruli shows marked increase in the amount of free cholesterol and phospholipids.[12]
  • Sea blue histiocytes on Wright-Giemsa are seen in bone marrow and spleen.[16]

Classification

Severity of the disease is a direct result of the enzyme deficiency. Mutation can cause either a complete loss of function or a partial loss of function, based on which LCAT deficiency can be classified into:[17]

  • Familial LCAT deficiency(FLD): Complete loss of alpha and beta LCAT function.
  • Fish Eye Disease (FED): Loss of alpha LCAT function and preserved beta fucntion.[18]
Familial LCAT deficiency (FLD) Fish Eye Disease (FED)
Enzyme Function Completely dysfunctional Loss of alpha function only
Clinical Features Corneal opacities, anaemia

and progressive renal disease with protienuria

Corneal opacities only

Normal renal function

Microscopy Deposition of FC and phospholipids

in cornea, RBC membrane and in the kidney.

Deposition of FC and phospolipids

in the cornea.

Laboratory findings Elevated Free cholesterol

HDL-C < 10 mg/dL[7]

Low Apo A1 and Apo A2

Elevated Apo E and Triglycerides

Low LDL C

Elevated free cholesterol

HDL C < 27 mg/dL

Apo A1＜30mg/dl and low Apo A2

Elevated Apo E and Triglycerides

Normal LDL and VLDL

Electrophoresis Pre β-1 and α-4 HDL, with β mobility due to

Lipoprotien-X

Pre β-1and α-4 HDL with normal

pre-β LDL.

Treatment Preserve kidney function

Kidney Transplant

Human recombinant enzyme replacement

Optimize lipid levels

Responds to statins[19]

Diagnosis

History and Symptoms

  • The most common clinical manifestaions in FLD include annular corneal opacity, hemolytic anemia and renal disease.[20]
  • Corneal opacities : First symptom in early childhood, starts at the limbus as an annular opacity resembling arcus lipoides senilis different from tangier disease where it is more central and dense, visual disturbances not common[21].
  • Hemolytic anemia : Excess free cholesterol and phospholipid deposition and increased phosphotidylcholine in the RBC membrane causes erythrocyte fragility[22]. patients present with jaundice, dyspnea and fatigue.
  • Renal disease : Proteinuria begins in adolescence and progresses to end stage renal disease requiring hemodialysis or transplantation in 30 to 40's, it presents with generalized swelling and hematuria.

Physical Exam

  • Bilateral annular corneal opacities characteristic of FLD and FED.
  • Other common findings include hypertension, pallor, pitting edema, icterus, splenomegaly.

Laboratory Findings

  • Very low HDL C [23]
  • High Unesterified cholesterol(UC) to total cholesterol ratio(TC).
  • Low Apo A1 and Apo A2 due to increased catabolism due to the failure in cholesterol ester formation which causes structural and composition changes in HDL.[24]
  • LDL has a characteristic morphology, large LDL C particles with high levels of free cholesterol, phospholipids with low cholesterol ester content, this is classed into lipoprotien X due to its mobility on electrophoresis.
  • Urine analysis show nephrotic range protienuria.

Electrophoresis

  • 2D gel Electrophoresis in FLD[25]:
    • Homozygotes have apoA-I in plasma present only in preβ-1 and α-4 discoidal HDL particles[26][9].
    • Heterozygotes for LCAT deficiency have less than 50% of normal large a-1 HDL, but two-fold increases in very small β 1 HDL.
    • Elevation in free cholesterol-enriched VLDL, has β instead of pre β mobility on electrophoresis.
    • Two-dimensional gel electrophoresis of whole plasma followed by immunoblotting with specific antibody for apoA-I can therefore readily be used to distinguish homozygous apoA-I deficiency, ABCA1 deficiency, or LCAT deficiency

Treatment

  • Mortality and morbidity of FLD is dependent on the progression of kidney disease.

Goals of therapy include:

  • Preserving kidney function
  • Control hypertension

Medical Therapy

  • No definitive treatment.
  • Recombinant human LCAT enzyme replacement has shown to improve to anemia, HDL C levels and stabilized kidney function[27] [28], but it is at the manufacturing stage.
  • High dose angiotensin receptor blockers help in improving the blood pressure, proteinuria and kidney function.[29]

Surgical Therapy

  • Patients are dependent on hemodialysis or should undergo renal transplant with worsening renal function but the lipid abnormalities recur[30].

References

  1. ↑ GLOMSET JA (1962). "The mechanism of the plasma cholesterol esterification reaction: plasma fatty acid transferase". Biochim Biophys Acta. 65: 128–35. PMID 13948499.
  2. ↑ Norum KR, Gjone E (1967). "Familial serum-cholesterol esterification failure. A new inborn error of metabolism". Biochim Biophys Acta. 144 (3): 698–700. PMID 6078131.
  3. ↑ Gjone E, Norum KR (1968). "Familial serum cholesterol ester deficiency. Clinical study of a patient with a new syndrome". Acta Med Scand. 183 (1–2): 107–12. PMID 5669813.
  4. ↑ McLean J, Wion K, Drayna D, Fielding C, Lawn R (1986). "Human lecithin-cholesterol acyltransferase gene: complete gene sequence and sites of expression". Nucleic Acids Res. 14 (23): 9397–406. PMC 311966. PMID 3797244.
  5. ↑ Goff DC, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R; et al. (2014). "2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Circulation. 129 (25 Suppl 2): S49–73. doi:10.1161/01.cir.0000437741.48606.98. PMID 24222018.
  6. ↑ Calabresi L, Baldassarre D, Castelnuovo S, Conca P, Bocchi L, Candini C; et al. (2009). "Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans". Circulation. 120 (7): 628–35. doi:10.1161/CIRCULATIONAHA.108.818143. PMID 19687369.
  7. ↑ 7.0 7.1 7.2 Ossoli A, Simonelli S, Vitali C, Franceschini G, Calabresi L (2016). "Role of LCAT in Atherosclerosis". J Atheroscler Thromb. 23 (2): 119–27. doi:10.5551/jat.32854. PMID 26607351.
  8. ↑ Chen CH, Albers JJ (1982). "Distribution of lecithin-cholesterol acyltransferase (LCAT) in human plasma lipoprotein fractions. Evidence for the association of active LCAT with low density lipoproteins". Biochem Biophys Res Commun. 107 (3): 1091–6. PMID 7138515.
  9. ↑ 9.0 9.1 Asztalos BF, Schaefer EJ, Horvath KV, Yamashita S, Miller M, Franceschini G; et al. (2007). "Role of LCAT in HDL remodeling: investigation of LCAT deficiency states". J Lipid Res. 48 (3): 592–9. doi:10.1194/jlr.M600403-JLR200. PMID 17183024.
  10. ↑ Tall AR (1990). "Plasma high density lipoproteins. Metabolism and relationship to atherogenesis". J Clin Invest. 86 (2): 379–84. doi:10.1172/JCI114722. PMC 296738. PMID 2200802.
  11. ↑ Narayanan S (1984). "Biochemistry and clinical relevance of lipoprotein X." Ann Clin Lab Sci. 14 (5): 371–4. PMID 6476782.
  12. ↑ 12.0 12.1 Ossoli A, Neufeld EB, Thacker SG, Vaisman B, Pryor M, Freeman LA; et al. (2016). "Lipoprotein X Causes Renal Disease in LCAT Deficiency". PLoS One. 11 (2): e0150083. doi:10.1371/journal.pone.0150083. PMC 4769176. PMID 26919698.
  13. ↑ Lynn EG, Siow YL, Frohlich J, Cheung GT, O K (2001). "Lipoprotein-X stimulates monocyte chemoattractant protein-1 expression in mesangial cells via nuclear factor-kappa B." Kidney Int. 60 (2): 520–32. doi:10.1046/j.1523-1755.2001.060002520.x. PMID 11473635.
  14. ↑ Funke H, von Eckardstein A, Pritchard PH, Hornby AE, Wiebusch H, Motti C; et al. (1993). "Genetic and phenotypic heterogeneity in familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Six newly identified defective alleles further contribute to the structural heterogeneity in this disease". J Clin Invest. 91 (2): 677–83. doi:10.1172/JCI116248. PMC 288009. PMID 8432868.
  15. ↑ Gotoda T, Yamada N, Murase T, Sakuma M, Murayama N, Shimano H; et al. (1991). "Differential phenotypic expression by three mutant alleles in familial lecithin:cholesterol acyltransferase deficiency". Lancet. 338 (8770): 778–81. PMID 1681161.
  16. ↑ Naghashpour M, Cualing H (2009). "Splenomegaly with sea-blue histiocytosis, dyslipidemia, and nephropathy in a patient with lecithin-cholesterol acyltransferase deficiency: a clinicopathologic correlation". Metabolism. 58 (10): 1459–64. doi:10.1016/j.metabol.2009.04.033. PMID 19592052.
  17. ↑ McIntyre N (1988). "Familial LCAT deficiency and fish-eye disease". J Inherit Metab Dis. 11 Suppl 1: 45–56. PMID 3141686.
  18. ↑ Funke H, von Eckardstein A, Pritchard PH, Albers JJ, Kastelein JJ, Droste C; et al. (1991). "A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity". Proc Natl Acad Sci U S A. 88 (11): 4855–9. PMC 51765. PMID 2052566.
  19. ↑ Dimick SM, Sallee B, Asztalos BF, Pritchard PH, Frohlich J, Schaefer EJ (2014). "A kindred with fish eye disease, corneal opacities, marked high-density lipoprotein deficiency, and statin therapy". J Clin Lipidol. 8 (2): 223–30. doi:10.1016/j.jacl.2013.11.005. PMID 24636183.
  20. ↑ Hrycek A, Cieślik P, Trzeciak HI (1994). "[Clinical features of lecithin-cholesterol acyltransferase deficiency]". Przegl Lek. 51 (12): 516–9. PMID 7746888.
  21. ↑ Hirano K, Kachi S, Ushida C, Naito M (2004). "Corneal and macular manifestations in a case of deficient lecithin: cholesterol acyltransferase". Jpn J Ophthalmol. 48 (1): 82–4. doi:10.1007/s10384-003-0007-1. PMID 14767661.
  22. ↑ Suda T, Akamatsu A, Nakaya Y, Masuda Y, Desaki J (2002). "Alterations in erythrocyte membrane lipid and its fragility in a patient with familial lecithin:cholesterol acyltrasferase (LCAT) deficiency". J Med Invest. 49 (3–4): 147–55. PMID 12323004.
  23. ↑ Saeedi R, Li M, Frohlich J (2015). "A review on lecithin:cholesterol acyltransferase deficiency". Clin Biochem. 48 (7–8): 472–5. doi:10.1016/j.clinbiochem.2014.08.014. PMID 25172171.
  24. ↑ Rader DJ, Ikewaki K, Duverger N, Schmidt H, Pritchard H, Frohlich J; et al. (1994). "Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease". J Clin Invest. 93 (1): 321–30. doi:10.1172/JCI116962. PMC 293770. PMID 8282802.
  25. ↑ Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF (2016). "Diagnosis and treatment of high density lipoprotein deficiency". Prog Cardiovasc Dis. 59 (2): 97–106. doi:10.1016/j.pcad.2016.08.006. PMID 27565770.
  26. ↑ Schaefer EJ, Santos RD, Asztalos BF (2010). "Marked HDL deficiency and premature coronary heart disease". Curr Opin Lipidol. 21 (4): 289–97. doi:10.1097/MOL.0b013e32833c1ef6. PMID 20616715.
  27. ↑ Shamburek RD, Bakker-Arkema R, Auerbach BJ, Krause BR, Homan R, Amar MJ; et al. (2016). "Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement". J Clin Lipidol. 10 (2): 356–67. doi:10.1016/j.jacl.2015.12.007. PMC 4826469. PMID 27055967.
  28. ↑ Simonelli S, Tinti C, Salvini L, Tinti L, Ossoli A, Vitali C; et al. (2013). "Recombinant human LCAT normalizes plasma lipoprotein profile in LCAT deficiency". Biologicals. 41 (6): 446–9. doi:10.1016/j.biologicals.2013.09.007. PMID 24140107.
  29. ↑ Aranda P, Valdivielso P, Pisciotta L, Garcia I, Garcã A-Arias C, Bertolini S; et al. (2008). "Therapeutic management of a new case of LCAT deficiency with a multifactorial long-term approach based on high doses of angiotensin II receptor blockers (ARBs)". Clin Nephrol. 69 (3): 213–8. PMID 18397721.
  30. ↑ Ahmad SB, Miller M, Hanish S, Bartlett ST, Hutson W, Barth RN; et al. (2016). "Sequential kidney-liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency". Clin Transplant. 30 (10): 1370–1374. doi:10.1111/ctr.12826. PMID 27490864.


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