Lecithin cholesterol acyltransferase deficiency: Difference between revisions

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{{Hypolipoproteinemia}}
{{SI}}
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{{CMG}} {{AE}} {{AKI}}
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{{SK}} LCAT deficiency, dyslipoproteinemic corneal dystrophy, fish eye disease, Norum disease, partial LCAT deficiency
{{SK}}LCAT deficiency, dyslipoproteinemic corneal dystrophy, fish eye disease, Norum disease, partial LCAT deficiency, Familial LCAT deficiency


==Overview==
==Overview==
[[Lecithin cholesterol acyltransferase]] ([[LCAT]]) is an [[enzyme]] with 2 subunits [[catalyzing]] the [[esterification]] of free [[cholesterol]] into [[cholesterol esters]], an important step in the [[reverse cholesterol transport]]. [[LCAT]] deficiency is a [[monogenic]] [[autosomal recessive]] disease resulting from mutation in the [[LCAT]] [[gene]] on [[chromosome]] number 16. Patients with [[homozygous]] and [[compound heterozygous]] [[mutations]] are symptomatic due to the accumulation of excessive free [[cholesterol]] in the [[cornea]], [[RBC]] [[cell membrane]] and the [[kidney]]. [[LCAT]] deficiency is classified into Familial [[LCAT]] deficiency(FLD) and Fish Eye Disease (FED) based on the degree of the [[enzyme]] function lost. The characteristic feature of these diseases is low plasma [[HDL]] C. FLD is a severe form with low [[HDL]] C and increase in [[LDL]] type protein called [[lipoprotein-X]] causing progressive [[renal failure]], FED has a benign course with [[corneal opacities]] and low [[HDL]] C alone. Low [[HDL]] is a risk factor for development of [[cardiovascular disease|cardiovascular disease,]]<ref name="pmid24222018">{{cite journal| author=Goff DC, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R et al.| title=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. | journal=Circulation | year= 2014 | volume= 129 | issue= 25 Suppl 2 | pages= S49-73 | pmid=24222018 | doi=10.1161/01.cir.0000437741.48606.98 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24222018  }} </ref>but the risk of developing [[atherosclerosis]] and cardiovascular disease in LCAT deficiency is still not well defined and is controversial.<ref name="pmid19687369">{{cite journal| author=Calabresi L, Baldassarre D, Castelnuovo S, Conca P, Bocchi L, Candini C et al.| title=Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans. | journal=Circulation | year= 2009 | volume= 120 | issue= 7 | pages= 628-35 | pmid=19687369 | doi=10.1161/CIRCULATIONAHA.108.818143 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19687369  }} </ref><ref name="pmid26607351">{{cite journal| author=Ossoli A, Simonelli S, Vitali C, Franceschini G, Calabresi L| title=Role of LCAT in Atherosclerosis. | journal=J Atheroscler Thromb | year= 2016 | volume= 23 | issue= 2 | pages= 119-27 | pmid=26607351 | doi=10.5551/jat.32854 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26607351  }} </ref>
==Historical Perspective==
==Historical Perspective==
*In 1962, Glomset identified an enzyme (plasma fatty acid transferase) which transfers fatty acid onto free cholesterol to make a cholesterol ester. This helps in the formation of a mature HDL particle a crucial step in reverse cholesterol transport <ref name="pmid13948499">{{cite journal| author=GLOMSET JA| title=The mechanism of the plasma cholesterol esterification reaction: plasma fatty acid transferase. | journal=Biochim Biophys Acta | year= 1962 | volume= 65 | issue=  | pages= 128-35 | pmid=13948499 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13948499  }} </ref>.
*In 1962, Glomset identified an enzyme ([[plasma]] [[fatty acid]] [[transferase]]) which transfers fatty acid onto free cholesterol forming a [[cholesterol ester]] helping in the formation of a mature HDL particle, a crucial step of reverse cholesterol transport. <ref name="pmid13948499">{{cite journal| author=GLOMSET JA| title=The mechanism of the plasma cholesterol esterification reaction: plasma fatty acid transferase. | journal=Biochim Biophys Acta | year= 1962 | volume= 65 | issue=  | pages= 128-35 | pmid=13948499 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13948499  }} </ref>
*In 1967, Norum and Gjone described a disease for the first time in a patient from Norway with features of normochromic anemia, protienuria and corneal lipid deposits<ref name="pmid6078131">{{cite journal| author=Norum KR, Gjone E| title=Familial serum-cholesterol esterification failure. A new inborn error of metabolism. | journal=Biochim Biophys Acta | year= 1967 | volume= 144 | issue= 3 | pages= 698-700 | pmid=6078131 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6078131  }} </ref>.
*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.<ref name="pmid6078131">{{cite journal| author=Norum KR, Gjone E| title=Familial serum-cholesterol esterification failure. A new inborn error of metabolism. | journal=Biochim Biophys Acta | year= 1967 | volume= 144 | issue= 3 | pages= 698-700 | pmid=6078131 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6078131  }} </ref>
*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. Foam cells in the bone marrow and glomerulus were demonstrated on microscopy. Patients had absent hepatomegaly and normal tonsils differentiating it from liver disease causing the defect in esterification and Tangier disease. Low serum cholesterol esters were attributed to the LCAT enzyme deficiency<ref name="pmid5669813">{{cite journal| author=Gjone E, Norum KR| title=Familial serum cholesterol ester deficiency. Clinical study of a patient with a new syndrome. | journal=Acta Med Scand | year= 1968 | volume= 183 | issue= 1-2 | pages= 107-12 | pmid=5669813 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5669813  }} </ref>.
*In 1967, Norum and Gjone reported two sisters of the affected patient had similar presentation along with low levels of [[cholesterol esters]] and [[Lysolecithin acylmutase|lysolecithin]] in the [[serum]], with increased total body [[cholesterol]], [[triglyceride]] and [[phospholipid]]. Other additional findings included were :
*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 <ref name="pmid3797244">{{cite journal| author=McLean J, Wion K, Drayna D, Fielding C, Lawn R| title=Human lecithin-cholesterol acyltransferase gene: complete gene sequence and sites of expression. | journal=Nucleic Acids Res | year= 1986 | volume= 14 | issue= 23 | pages= 9397-406 | pmid=3797244 | doi= | pmc=311966 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3797244  }} </ref> and is synthesized mainly in the liver.
**[[Foam cells]] were demonstrated in [[bone marrow]] and [[glomerulus]] on [[microscopy]].  
**Patients had absent [[hepatomegaly]] differentiating it from [[liver disease]] causing the defect in esterification.
**Patients had normal [[tonsils]] differentiating it from [[Tangier disease]].  
**Low [[serum]] [[cholesterol esters]] were attributed to the [[LCAT]] [[enzyme]] deficiency.<ref name="pmid5669813">{{cite journal| author=Gjone E, Norum KR| title=Familial serum cholesterol ester deficiency. Clinical study of a patient with a new syndrome. | journal=Acta Med Scand | year= 1968 | volume= 183 | issue= 1-2 | pages= 107-12 | pmid=5669813 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5669813  }} </ref>
*In 1986, McLean and colleagues reported the complete [[gene sequence]] and the sites of expression on [[lecithin cholesterol acyl transferase]] [[gene]] (LCAT). The location of the gene is identified to be on q21-22 region of [[chromosome 16]]. <ref name="pmid3797244">{{cite journal| author=McLean J, Wion K, Drayna D, Fielding C, Lawn R| title=Human lecithin-cholesterol acyltransferase gene: complete gene sequence and sites of expression. | journal=Nucleic Acids Res | year= 1986 | volume= 14 | issue= 23 | pages= 9397-406 | pmid=3797244 | doi= | pmc=311966 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3797244  }} </ref>
 
==Classification==
[[LCAT]] deficiency is classified based on the quantity of [[enzyme]] function defective. A [[mutation]] in the [[LCAT]] [[gene]] can cause either a complete loss of function or a partial loss of function which is the basis of [[LCAT]] deficiency classification:<ref name="pmid3141686">{{cite journal| author=McIntyre N| title=Familial LCAT deficiency and fish-eye disease. | journal=J Inherit Metab Dis | year= 1988 | volume= 11 Suppl 1 | issue=  | pages= 45-56 | pmid=3141686 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3141686  }} </ref>
*Familial LCAT deficiency(FLD): Complete loss of alpha and beta [[LCAT]] function.
*Fish Eye Disease (FED): Loss of alpha LCAT function with preserved beta function.<ref name="pmid2052566">{{cite journal| author=Funke H, von Eckardstein A, Pritchard PH, Albers JJ, Kastelein JJ, Droste C et al.| title=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. | journal=Proc Natl Acad Sci U S A | year= 1991 | volume= 88 | issue= 11 | pages= 4855-9 | pmid=2052566 | doi= | pmc=51765 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2052566  }} </ref>
{| class="wikitable"
!
!Familial LCAT deficiency (FLD)
!Fish Eye Disease (FED)
|-
|[[Enzyme Function]]
|Completely dysfunctional
|Loss of alpha function only
|-
|Clinical Features
|Corneal [[Opacity|opacities]], [[anaemia]]
and progressive renal disease with proteinuria
|Corneal opacities only;
Normal renal function
|-
|Microscopy
|Deposition of free [[cholesterol]] and [[phospholipids]] in [[cornea]], [[RBC]] [[cell membrane]] and in the [[kidney]]
|Deposition of free [[cholesterol]] and [[phospholipids]] in the [[cornea]]
|-
|Laboratory findings
|Elevated free [[cholesterol]]
[[HDL]]C < 10 mg/dL<ref name="pmid26607351">{{cite journal| author=Ossoli A, Simonelli S, Vitali C, Franceschini G, Calabresi L| title=Role of LCAT in Atherosclerosis. | journal=J Atheroscler Thromb | year= 2016 | volume= 23 | issue= 2 | pages= 119-27 | pmid=26607351 | doi=10.5551/jat.32854 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26607351  }} </ref>
Low [[Apo A1]] and [[Apo AII]]
Elevated [[Apo E]] and [[triglycerides]]
Low [[LDL]] C
|Elevated free [[cholesterol]]
[[HDL]] C < 27 mg/dL 
 
[[Apo A1]]<30mg/dl and low [[Apo AII]]
 
Elevated [[Apo E]] and [[triglycerides]]
 
Normal [[LDL]] and [[VLDL]]
|-
|Electrophoresis
|Pre β-1 and α-4 [[HDL]], [[LDL]] C with β mobility due to
[[Lipoprotien-X]]
|Pre β-1and α-4 [[HDL]] with normal
pre-β [[LDL]]
|-
|Treatment
|Preserve kidney function
[[Kidney transplant]]


==Demographics, Natural History and Complications==
Human [[recombinant enzyme replacement]]
|Optimize lipid levels
Responds to statins<ref name="pmid24636183">{{cite journal| author=Dimick SM, Sallee B, Asztalos BF, Pritchard PH, Frohlich J, Schaefer EJ| title=A kindred with fish eye disease, corneal opacities, marked high-density lipoprotein deficiency, and statin therapy. | journal=J Clin Lipidol | year= 2014 | volume= 8 | issue= 2 | pages= 223-30 | pmid=24636183 | doi=10.1016/j.jacl.2013.11.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24636183  }} </ref>
|}


==Pathophysiology==
==Pathophysiology==


===Pathogenesis===
===Pathogenesis===
LCAT deficiency is caused by a mutation in the [[LCAT]] [[gene]], resulting in disruption of the [[reverse cholesterol transport]].


====LCAT Function====
====LCAT Function====
*Majority of the enzyme is associated with HDL C, very small amount with LDL C<ref name="pmid7138515">{{cite journal| author=Chen CH, Albers JJ| title=Distribution of lecithin-cholesterol acyltransferase (LCAT) in human plasma lipoprotein fractions. Evidence for the association of active LCAT with low density lipoproteins. | journal=Biochem Biophys Res Commun | year= 1982 | volume= 107 | issue= 3 | pages= 1091-6 | pmid=7138515 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7138515  }} </ref>.
{{Family tree/start}}
{{Family tree/start}}
{{Family tree | | | | A01 | | | |A01= LCAT synthesized in liver and released into circulation and is picked up by HDL C}}
{{Family tree | | | | A01 | | | |A01= [[LCAT]] is synthesized in [[liver]] and released into circulation and is picked up by [[HDL]] C}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | B01 | | | |B01= Apo A1 activates LCAT}}
{{Family tree | | | | B01 | | | |B01= [[Apo A1]] activates LCAT associated with [[HDL]], [[Apo E]] activates [[LCAT]] associated with [[LDL]] C}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | C01 | | | |C01= LCAT cleaves fatty acid from phosphotidylcholine}}
{{Family tree | | | | C01 | | | |C01= [[LCAT]] cleaves fatty acid from [[phosphotidylcholine]]}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | D01 | | | |D01= Transfers fatty acid to beta hydroxyl group of free cholesterol(FC) taken up by HDL C}}
{{Family tree | | | | D01 | | | |D01= Transfers fatty acid to beta hydroxyl group of free cholesterol taken up by [[HDL]] C}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | E01 | | | |E01= Results in the formation of cholesterol esters which
{{Family tree | | | | E01 | | | |E01= Results in the formation of [[cholesterol esters]] which
help in maturation of HDL C and also forms lysophosphotidylcholine}}
help in maturation of HDL C and also forms lysophosphotidylcholine}}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | |!| | | | | }}
{{Family tree | | | | F01 | | | |F01= Esterification of FC taken up by HDL C, is Alpha LCAT activity.
{{Family tree | | | | F01 | | | |F01= Esterification of free cholesterol 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}}
Esterification of free [[cholesterol]] associated with [[Apo B]]( LDL C), is β-LCAT activity. This differentiation into alpha and beta is based on the [[HDL]] and [[LDL]] mobility on electrophoresis<ref name="pmid17183024">{{cite journal| author=Asztalos BF, Schaefer EJ, Horvath KV, Yamashita S, Miller M, Franceschini G et al.| title=Role of LCAT in HDL remodeling: investigation of LCAT deficiency states. | journal=J Lipid Res | year= 2007 | volume= 48 | issue= 3 | pages= 592-9 | pmid=17183024 | doi=10.1194/jlr.M600403-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17183024  }} </ref>}}
{{Family tree/end}}
{{Family tree/end}}


*Majority of the enzyme is associated with [[HDL]] C; only a very minor amount is associated with [[LDL]] C.<ref name="pmid7138515">{{cite journal| author=Chen CH, Albers JJ| title=Distribution of lecithin-cholesterol acyltransferase (LCAT) in human plasma lipoprotein fractions. Evidence for the association of active LCAT with low density lipoproteins. | journal=Biochem Biophys Res Commun | year= 1982 | volume= 107 | issue= 3 | pages= 1091-6 | pmid=7138515 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7138515  }} </ref>
*LCAT helps in reverse cholesterol transport by:<ref name="pmid2200802">{{cite journal| author=Tall AR| title=Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. | journal=J Clin Invest | year= 1990 | volume= 86 | issue= 2 | pages= 379-84 | pmid=2200802 | doi=10.1172/JCI114722 | pmc=296738 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2200802  }} </ref>
*LCAT helps in reverse cholesterol transport by:<ref name="pmid2200802">{{cite journal| author=Tall AR| title=Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. | journal=J Clin Invest | year= 1990 | volume= 86 | issue= 2 | pages= 379-84 | pmid=2200802 | doi=10.1172/JCI114722 | pmc=296738 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2200802  }} </ref>
**Cholesterol esters due to the hydrophobic nature occupy the core of the lipoprotien, which prevent the backflow of cholesterol into the cells.
**[[Cholesterol esters]] are hydrophobic and occupy the core of the [[lipoprotien]] preventing backflow of [[cholesterol]] back 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.
**Promoting 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====
====LCAT Deficiency====
{{Family tree/start}}
{{Family tree/start}}
{{Family tree | | | | A01 | | | |A01= Loss of LCAT function}}
{{Family tree | | | | A01 | | | |A01= Loss of [[LCAT]] function}}
{{Family tree | |,|-|-|^|-|-|.| | }}
{{Family tree | |,|-|-|^|-|-|.| | }}
{{Family tree | B01 | | | | B02 |B01= 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|B02= Loss of beta function results in elevated FC, phospholipids and formation of cholesterol rich particle called Lipoprotien X <ref name="pmid6476782">{{cite journal| author=Narayanan S| title=Biochemistry and clinical relevance of lipoprotein X. | journal=Ann Clin Lab Sci | year= 1984 | volume= 14 | issue= 5 | pages= 371-4 | pmid=6476782 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6476782  }} </ref>, which are implicated in the development of glomerulopathy<ref name="pmid26919698">{{cite journal| author=Ossoli A, Neufeld EB, Thacker SG, Vaisman B, Pryor M, Freeman LA et al.| title=Lipoprotein X Causes Renal Disease in LCAT Deficiency. | journal=PLoS One | year= 2016 | volume= 11 | issue= 2 | pages= e0150083 | pmid=26919698 | doi=10.1371/journal.pone.0150083 | pmc=4769176 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26919698  }} </ref>.
{{Family tree | B01 | | | | B02 |B01= Loss of alpha function leads to failure of HDL maturation resulting in elevated FC, phospholipids, Apo E, pre beta HDL, and low Apo A1 and Apo A2 levels|B02= Loss of beta function results in elevated FC, phospholipids, and formation of cholesterol rich multilamellar particles called Lipoprotein X <ref name="pmid6476782">{{cite journal| author=Narayanan S| title=Biochemistry and clinical relevance of lipoprotein X. | journal=Ann Clin Lab Sci | year= 1984 | volume= 14 | issue= 5 | pages= 371-4 | pmid=6476782 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6476782  }} </ref>, which are implicated in the development of [[glomerulopathy]]<ref name="pmid26919698">{{cite journal| author=Ossoli A, Neufeld EB, Thacker SG, Vaisman B, Pryor M, Freeman LA et al.| title=Lipoprotein X Causes Renal Disease in LCAT Deficiency. | journal=PLoS One | year= 2016 | volume= 11 | issue= 2 | pages= e0150083 | pmid=26919698 | doi=10.1371/journal.pone.0150083 | pmc=4769176 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26919698 }} </ref> <ref name="pmid11473635">{{cite journal| author=Lynn EG, Siow YL, Frohlich J, Cheung GT, O K| title=Lipoprotein-X stimulates monocyte chemoattractant protein-1 expression in mesangial cells via nuclear factor-kappa B. | journal=Kidney Int | year= 2001 | volume= 60 | issue= 2 | pages= 520-32 | pmid=11473635 | doi=10.1046/j.1523-1755.2001.060002520.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11473635 }} </ref>.
  }}
  }}
{{Family tree/end}}
{{Family tree/end}}


===Genetics===
===Genetics===
*Autosomal Recessive.
LCAT deficiency presents the following genetic characteristics:
*LCAT gene is on chromosome 16.
*LCAT deficiency is transmitted in a [[autosomal recessive]] inheritance.
*Expression of clinical features and severity of disease in homozygous patients depends on the type and locus of the mutation<ref name="pmid1681161">{{cite journal| author=Gotoda T, Yamada N, Murase T, Sakuma M, Murayama N, Shimano H et al.| title=Differential phenotypic expression by three mutant alleles in familial lecithin:cholesterol acyltransferase deficiency. | journal=Lancet | year= 1991 | volume= 338 | issue= 8770 | pages= 778-81 | pmid=1681161 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1681161  }} </ref>.
*LCAT gene is located on [[chromosome]] 16, and multiple mutation sites have been identified.<ref name="pmid8432868">{{cite journal| author=Funke H, von Eckardstein A, Pritchard PH, Hornby AE, Wiebusch H, Motti C et al.| title=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. | journal=J Clin Invest | year= 1993 | volume= 91 | issue= 2 | pages= 677-83 | pmid=8432868 | doi=10.1172/JCI116248 | pmc=288009 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8432868  }} </ref>
*The expression of clinical features and severity of disease in [[homozygous]] patients is determined by the type and [[locus]] of the [[mutation]].<ref name="pmid1681161">{{cite journal| author=Gotoda T, Yamada N, Murase T, Sakuma M, Murayama N, Shimano H et al.| title=Differential phenotypic expression by three mutant alleles in familial lecithin:cholesterol acyltransferase deficiency. | journal=Lancet | year= 1991 | volume= 338 | issue= 8770 | pages= 778-81 | pmid=1681161 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1681161  }} </ref>
*[[Heterozygous]] patients have an intermediate biochemical expression with reduced plasma [[HDL]]C and [[Apo A1]] levels.<ref name="pmid26607351">{{cite journal| author=Ossoli A, Simonelli S, Vitali C, Franceschini G, Calabresi L| title=Role of LCAT in Atherosclerosis. | journal=J Atheroscler Thromb | year= 2016 | volume= 23 | issue= 2 | pages= 119-27 | pmid=26607351 | doi=10.5551/jat.32854 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26607351  }} </ref>


===Microscopy===
===Microscopy===
Microscopic and histopathological examinations of tissues in [[LCAT]] deficiency will reveal the following:
*Deposition of free cholesterol and phospholipids in the cornea and RBC membrane.
*Kidney [[biopsy]] in the early stage of the disease show mild [[mesangium]] enlargement and thickening of [[Glomerular basement membrane|glomerular basement membrane (GBM)]].
**[[Lipid]] filled foamy deposits are demonstrated in the [[glomerular basement membrane]].
**[[Lipid analysis]] of isolated [[glomeruli]] show marked increase in the amount of free [[cholesterol]] and [[phospholipids]].<ref name="pmid26919698">{{cite journal| author=Ossoli A, Neufeld EB, Thacker SG, Vaisman B, Pryor M, Freeman LA et al.| title=Lipoprotein X Causes Renal Disease in LCAT Deficiency. | journal=PLoS One | year= 2016 | volume= 11 | issue= 2 | pages= e0150083 | pmid=26919698 | doi=10.1371/journal.pone.0150083 | pmc=4769176 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26919698  }} </ref>
*Sea blue [[histiocytes]] on [[Wright-Giemsa]] are observed in [[bone marrow]] and [[spleen]].<ref name="pmid19592052">{{cite journal| author=Naghashpour M, Cualing H| title=Splenomegaly with sea-blue histiocytosis, dyslipidemia, and nephropathy in a patient with lecithin-cholesterol acyltransferase deficiency: a clinicopathologic correlation. | journal=Metabolism | year= 2009 | volume= 58 | issue= 10 | pages= 1459-64 | pmid=19592052 | doi=10.1016/j.metabol.2009.04.033 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19592052  }} </ref>
== Epidemiology and Demographics ==
*The prevalence of Familial [[LCAT]] deficiency rare and is estimated to be less than 1/1,000,000. About 125 cases have been reported to date worldwide.<ref name="urlOrphanet: LCAT deficiency">{{cite web |url=http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=650 |title=Orphanet: LCAT deficiency |format= |work= |accessdate=}}</ref>
*Majority of the cases are reported in Europe, Japan and Canada.
==Natural History, Complications and Prognosis ==
*If left untreated, patients with FLD will develop progressive decline in [[renal function]], resulting in [[end stage renal disease]].
*[[Corneal opacities]] are the earliest manifestation and appear in early childhood; it usually starts at the [[limbus]] as an annular opacity resembling [[Arcus lipoides corneae|arcus lipoides]] senilis which is different from [[Tangier disease]] where it is more central and dense.Visual disturbances are not common.<ref name="pmid14767661">{{cite journal| author=Hirano K, Kachi S, Ushida C, Naito M| title=Corneal and macular manifestations in a case of deficient lecithin: cholesterol acyltransferase. | journal=Jpn J Ophthalmol | year= 2004 | volume= 48 | issue= 1 | pages= 82-4 | pmid=14767661 | doi=10.1007/s10384-003-0007-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14767661  }} </ref>
*[[Hemolytic anemia]] results from excessive free [[cholesterol]], [[phospholipid]] deposition, and increased [[phosphotidylcholine]] in the [[RBC]] membrane causing [[erythrocyte]] fragility.<ref name="pmid12323004">{{cite journal| author=Suda T, Akamatsu A, Nakaya Y, Masuda Y, Desaki J| title=Alterations in erythrocyte membrane lipid and its fragility in a patient with familial lecithin:cholesterol acyltrasferase (LCAT) deficiency. | journal=J Med Invest | year= 2002 | volume= 49 | issue= 3-4 | pages= 147-55 | pmid=12323004 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12323004  }} </ref>
*[[Renal disease]] is the major complication and begins in [[adolescence]] with [[proteinuria]] and progresses to [[end stage renal disease]] requiring [[hemodialysis]] or [[transplantation]] in the patient's 30's and 40's
*Mortality and morbidity of FLD is dependent on the progression of kidney disease and prognosis is poor.
*FED has a benign course.
==Diagnosis==
=== History and Symptoms ===
The most common features of clinical presentation include annular [[corneal opacity]], [[hemolytic anemia]] and [[renal disease]].<ref name="pmid7746888">{{cite journal| author=Hrycek A, Cieślik P, Trzeciak HI| title=[Clinical features of lecithin-cholesterol acyltransferase deficiency]. | journal=Przegl Lek | year= 1994 | volume= 51 | issue= 12 | pages= 516-9 | pmid=7746888 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7746888  }} </ref> The common presenting features include:
*[[Corneal]] opacities in childhood
*[[Fatigue]]
*[[Dyspnea]] on [[exertion]]
*[[Jaundice]]
*Generalized [[body swelling]]
*[[Bloody urine]]
*Less common presenting features include:
**Abdominal discomfort
**[[Palpitations]]
===Physical Examination===
Physical examination of patients with LCAT deficiency is remarkable for the following:
*Bilateral annular [[corneal opacities]], characteristic clinical manifestation of FLD and FED
*[[Hepatomegaly]] and [[splenomegaly]]
*[[Icterus]]
*[[Pallor]]
===Laboratory Findings===
Laboratory findings consistent with the diagnosis of Familial [[LCAT]] deficiency include:
*Very low [[HDL]] C levels <ref name="pmid25172171">{{cite journal| author=Saeedi R, Li M, Frohlich J| title=A review on lecithin:cholesterol acyltransferase deficiency. | journal=Clin Biochem | year= 2015 | volume= 48 | issue= 7-8 | pages= 472-5 | pmid=25172171 | doi=10.1016/j.clinbiochem.2014.08.014 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25172171  }} </ref>
*High unesterified cholesterol(UC) to total cholesterol ratio (TC) is the characteristic laboratory finding.
*Low [[Apo A1]] and [[Apo AII]] levels due to increased [[catabolism]] resulting from the failure in [[cholesterol ester]] formation, causing structural and composition changes in [[HDL]] C particles.<ref name="pmid8282802">{{cite journal| author=Rader DJ, Ikewaki K, Duverger N, Schmidt H, Pritchard H, Frohlich J et al.| title=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. | journal=J Clin Invest | year= 1994 | volume= 93 | issue= 1 | pages= 321-30 | pmid=8282802 | doi=10.1172/JCI116962 | pmc=293770 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8282802  }} </ref>
*[[LDL]] C in these patients displays a characteristic morphology with large [[LDL]] C particles containing high levels of free [[cholesterol]], [[phospholipids]] and low [[cholesterol ester]] content.
**This is classed into [[lipoprotein X]] due to its beta-mobility on [[electrophoresis]].
*[[Urinalysis]] show [[nephrotic]] range [[proteinuria]].
====Electrophoresis====
2D gel electrophoresis in FLD is remarkable for the following:<ref name="pmid27565770">{{cite journal| author=Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF| title=Diagnosis and treatment of high density lipoprotein deficiency. | journal=Prog Cardiovasc Dis | year= 2016 | volume= 59 | issue= 2 | pages= 97-106 | pmid=27565770 | doi=10.1016/j.pcad.2016.08.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27565770  }} </ref>
* [[Homozygotes]] have [[Apo A1]] in [[plasma]] present only in preβ-1 and α-4 discoidal [[HDL]] particles after [[Apo A1]] [[immunoblotting]].<ref name="pmid20616715">{{cite journal| author=Schaefer EJ, Santos RD, Asztalos BF| title=Marked HDL deficiency and premature coronary heart disease. | journal=Curr Opin Lipidol | year= 2010 | volume= 21 | issue= 4 | pages= 289-97 | pmid=20616715 | doi=10.1097/MOL.0b013e32833c1ef6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20616715  }} </ref><ref name="pmid17183024">{{cite journal| author=Asztalos BF, Schaefer EJ, Horvath KV, Yamashita S, Miller M, Franceschini G et al.| title=Role of LCAT in HDL remodeling: investigation of LCAT deficiency states. | journal=J Lipid Res | year= 2007 | volume= 48 | issue= 3 | pages= 592-9 | pmid=17183024 | doi=10.1194/jlr.M600403-JLR200 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17183024  }} </ref>
*[[Heterozygotes]] for [[LCAT]] deficiency have less than 50% of normal large alpha-1 [[HDL]], but two-fold increases in very small beta-1 [[HDL]] C.
*Elevation in free [[cholesterol]]-enriched [[VLDL|LDL]]<nowiki/>hCaving β betanmobility stead of pre β mobility.
*Two-dimensional gel [[electrophoresis]] after [[immunoblotting]] with specific antibody for [[Apo A1]] helps differentiate between [[homozygous]] [[Apo A1]] deficiency, [[ABCA1]] deficiency and [[LCAT]] deficiency.


==Classification==
==Low HDL C differential diagnosis==
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:<ref name="pmid3141686">{{cite journal| author=McIntyre N| title=Familial LCAT deficiency and fish-eye disease. | journal=J Inherit Metab Dis | year= 1988 | volume= 11 Suppl 1 | issue=  | pages= 45-56 | pmid=3141686 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3141686  }} </ref>
*Familial LCAT deficiency: Complete loss of alpha and beta LCAT function.
*Fish Eye Disease: Loss of alpha LCAT function and preserved beta fucntion.
{| class="wikitable"
{| class="wikitable"
!
!
!Familial LCAT deficiency
!Familial LCAT  
!Fish Eye Disease
Deficiency
!Fish Eye  
Disease
!Homozygous Tangier
Disease
!Heterozygous Tangier
Disease
!Apo A1 Deficiency
|-
|Gene Defect
|LCAT
|LCAT
|ABCA1
|ABCA1
|Apo A1
|-
|Inheritance
|Autosomal Recessive
|Autosomal Recessive
|Autosomal Recessive
|Autosomal Recessive
|Autosomal Dominant
|-
|-
|Enzyme Defect
|Pathogenesis
|Complete loss
|
*Loss of alpha and beta LCAT function
*Failure of cholesterol ester formation.
|Loss of alpha function only
|Loss of alpha function only
|
Pre beta-1 HDL fails to picks up free cholesterol from cells due to mutation in ABCA1 transporter.
|Similar to homozygous
|Defective synthesis of Apo A1 resulting in failure of maturation of HDL and defective reverse cholesterol transport.
|-
|-
|Clinical Features
|Clinical Features
|Corneal opacities, anaemia
|
and progressive renal disease with protienuria
*Annular corneal opacity
|Corneal opacities only
*Anaemia
Normal renal function  
*Progressive renal disease with proteinuria
|-
|
|Microscopy
*Corneal opacities only
|Deposition of FC and phospholipids
*Normal renal function
in cornea and RBC membrane.
|
*Large yellow-orange tonsils
 
*Dense central corneal opacity


Lipoprotien-X deposition in the glomerulus.
*Relapsing and remitting course of neuropathy
|Deposition of FC and phospolipids
|Asymptomatic
in the cornea.
|
*Corneal Opacities
*Tuboeruptive, Planar and palmar Xanthomas
*Premature Heart Disease
|-
|-
|Laboratory findings
|Lipid Panel
|Elevated Free cholesterol  
|
Very low HDL C
*Elevated Free cholesterol
 
Low Apo A1 and Apo A2


Elevated Apo E
*HDL-C < 10 mg/dL


Low LDL C
*Low Apo A1 and Apo AII
|Elevated free cholesterol
Very low HDL C


Low Apo A1 and Apo A2
*Elevated Apo E and Triglycerides


Elevated Apo E
*Low LDL C
|
*Elevated free cholesterol


Normal LDL and VLDL
*HDL C < 27 mg/dL
|}


==Diagnosis==
*Apo A1<30mg/dl and low Apo A2


===History and Symptoms===
*Elevated Apo E and Triglycerides


===Laboratory Findings===
*Normal LDL and VLDL
|
*HDL < 5% of normal


===Others===
*Apo A1 < 1% of normal


*LDL < 40% of normal
|
*HDL C, Apo A1 and  LDL 50% less than normal.
|
*Undetectable Apo A1
*HDL C less than 10mg/dl
*Normal or low Apo AII
*LDL C normal
*Triglyceride normal or elevated 
|-
|2D Gel Electrophoresis
|Pre β-1 and α-4 HDL, LDL with  β mobility due to Lipoprotien-X
|Pre β-1and α-4 HDL with normal pre-β LDL.
|Only preβ-1 HDL present
|
*Lack of large α-1 and α-2 HDL particles
*Normal preβ-1 HDL
|Lack of Apo A1 containing HDL particles.
|}


==Treatment==
==Treatment==
===Medical Therapy===
The mainstay of therapy for Familial [[LCAT]] deficiency include:
*Preserving kidney function
*Controlling [[hypertension]]
While there is no definitive medical therapy to treat LCAT deficiency, the following methods can help mitigate complications and alleviate symptoms:
*Recombinant human [[LCAT]] enzyme replacement has shown to improve [[anemia]] and [[HDL]] C levels and to preserve kidney function.<ref name="pmid27055967">{{cite journal| author=Shamburek RD, Bakker-Arkema R, Auerbach BJ, Krause BR, Homan R, Amar MJ et al.| title=Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 2 | pages= 356-67 | pmid=27055967 | doi=10.1016/j.jacl.2015.12.007 | pmc=4826469 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27055967  }} </ref> <ref name="pmid24140107">{{cite journal| author=Simonelli S, Tinti C, Salvini L, Tinti L, Ossoli A, Vitali C et al.| title=Recombinant human LCAT normalizes plasma lipoprotein profile in LCAT deficiency. | journal=Biologicals | year= 2013 | volume= 41 | issue= 6 | pages= 446-9 | pmid=24140107 | doi=10.1016/j.biologicals.2013.09.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24140107  }} </ref>
**Currently it is at the manufacturing stage and is not yet available for widespread use.
*High dose [[angiotensin receptor]] blockers help in improving [[blood pressure]], [[proteinuria]] and kidney function.<ref name="pmid18397721">{{cite journal| author=Aranda P, Valdivielso P, Pisciotta L, Garcia I, Garcã A-Arias C, Bertolini S et al.| title=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). | journal=Clin Nephrol | year= 2008 | volume= 69 | issue= 3 | pages= 213-8 | pmid=18397721 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18397721  }} </ref>


===Medical Therapy===
===Surgery===
*Patients dependent on [[hemodialysis]] with worsening renal function are indicated for [[renal transplant]].
**Lipid abnormalities usually recur after a renal transplant .<ref name="pmid27490864">{{cite journal| author=Ahmad SB, Miller M, Hanish S, Bartlett ST, Hutson W, Barth RN et al.| title=Sequential kidney-liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency. | journal=Clin Transplant | year= 2016 | volume= 30 | issue= 10 | pages= 1370-1374 | pmid=27490864 | doi=10.1111/ctr.12826 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27490864  }} </ref>
 
==Prevention==
*There are no screening recommendations for the disease. Patients are advised regular follow up, medication compliance and monitoring of the renal function to prevent progressive decline in renal function.


===Surgical Therapy===
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


[[Category:Cardiology]]


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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, Familial LCAT deficiency

Overview

Lecithin cholesterol acyltransferase (LCAT) is an enzyme with 2 subunits catalyzing the esterification of free cholesterol into cholesterol esters, an important step in the reverse cholesterol transport. LCAT deficiency is a monogenic autosomal recessive disease resulting from mutation in the LCAT gene on chromosome number 16. Patients with homozygous and compound heterozygous mutations are symptomatic due to the accumulation of excessive free cholesterol in the cornea, RBC cell membrane and the kidney. LCAT deficiency is classified into Familial LCAT deficiency(FLD) and Fish Eye Disease (FED) based on the degree of the enzyme function lost. The characteristic feature of these diseases is low plasma HDL C. FLD is a severe form with low HDL C and increase in LDL type protein called lipoprotein-X causing progressive renal failure, FED has a benign course with corneal opacities and low HDL C alone. Low HDL is a risk factor for development of cardiovascular disease,[1]but the risk of developing atherosclerosis and cardiovascular disease in LCAT deficiency is still not well defined and is controversial.[2][3]

Historical Perspective

Classification

LCAT deficiency is classified based on the quantity of enzyme function defective. A mutation in the LCAT gene can cause either a complete loss of function or a partial loss of function which is the basis of LCAT deficiency classification:[8]

  • Familial LCAT deficiency(FLD): Complete loss of alpha and beta LCAT function.
  • Fish Eye Disease (FED): Loss of alpha LCAT function with preserved beta function.[9]
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 proteinuria

Corneal opacities only;

Normal renal function

Microscopy Deposition of free cholesterol and phospholipids in cornea, RBC cell membrane and in the kidney Deposition of free cholesterol and phospholipids in the cornea
Laboratory findings Elevated free cholesterol

HDLC < 10 mg/dL[3] Low Apo A1 and Apo AII Elevated Apo E and triglycerides Low LDL C

Elevated free cholesterol

HDL C < 27 mg/dL

Apo A1<30mg/dl and low Apo AII

Elevated Apo E and triglycerides

Normal LDL and VLDL

Electrophoresis Pre β-1 and α-4 HDL, LDL C 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[10]

Pathophysiology

Pathogenesis

LCAT deficiency is caused by a mutation in the LCAT gene, resulting in disruption of the reverse cholesterol transport.

LCAT Function

 
 
 
LCAT is synthesized in liver and released into circulation and is picked up by HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apo A1 activates LCAT associated with 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 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 free cholesterol taken up by HDL C, is α-LCAT activity. Esterification of free cholesterol associated with Apo B( LDL C), is β-LCAT activity. This differentiation into alpha and beta is based on the HDL and LDL mobility on electrophoresis[11]
 
 
 

LCAT Deficiency

 
 
 
Loss of LCAT function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Loss of alpha function leads to failure of HDL maturation resulting in elevated FC, phospholipids, Apo E, 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 particles called Lipoprotein X [14], which are implicated in the development of glomerulopathy[15] [16].

Genetics

LCAT deficiency presents the following genetic characteristics:

Microscopy

Microscopic and histopathological examinations of tissues in LCAT deficiency will reveal the following:

Epidemiology and Demographics

  • The prevalence of Familial LCAT deficiency rare and is estimated to be less than 1/1,000,000. About 125 cases have been reported to date worldwide.[20]
  • Majority of the cases are reported in Europe, Japan and Canada.

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

The most common features of clinical presentation include annular corneal opacity, hemolytic anemia and renal disease.[23] The common presenting features include:

Physical Examination

Physical examination of patients with LCAT deficiency is remarkable for the following:

Laboratory Findings

Laboratory findings consistent with the diagnosis of Familial LCAT deficiency include:

Electrophoresis

2D gel electrophoresis in FLD is remarkable for the following:[26]

Low HDL C differential diagnosis

Familial LCAT

Deficiency

Fish Eye

Disease

Homozygous Tangier

Disease

Heterozygous Tangier

Disease

Apo A1 Deficiency
Gene Defect LCAT LCAT ABCA1 ABCA1 Apo A1
Inheritance Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Dominant
Pathogenesis
  • Loss of alpha and beta LCAT function
  • Failure of cholesterol ester formation.
Loss of alpha function only

Pre beta-1 HDL fails to picks up free cholesterol from cells due to mutation in ABCA1 transporter.

Similar to homozygous Defective synthesis of Apo A1 resulting in failure of maturation of HDL and defective reverse cholesterol transport.
Clinical Features
  • Annular corneal opacity
  • Anaemia
  • Progressive renal disease with proteinuria
  • Corneal opacities only
  • Normal renal function
  • Large yellow-orange tonsils
  • Dense central corneal opacity
  • Relapsing and remitting course of neuropathy
Asymptomatic
  • Corneal Opacities
  • Tuboeruptive, Planar and palmar Xanthomas
  • Premature Heart Disease
Lipid Panel
  • Elevated Free cholesterol
  • HDL-C < 10 mg/dL
  • Low Apo A1 and Apo AII
  • 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
  • HDL < 5% of normal
  • Apo A1 < 1% of normal
  • LDL < 40% of normal
  • HDL C, Apo A1 and LDL 50% less than normal.
  • Undetectable Apo A1
  • HDL C less than 10mg/dl
  • Normal or low Apo AII
  • LDL C normal
  • Triglyceride normal or elevated
2D Gel Electrophoresis Pre β-1 and α-4 HDL, LDL with β mobility due to Lipoprotien-X Pre β-1and α-4 HDL with normal pre-β LDL. Only preβ-1 HDL present
  • Lack of large α-1 and α-2 HDL particles
  • Normal preβ-1 HDL
Lack of Apo A1 containing HDL particles.

Treatment

Medical Therapy

The mainstay of therapy for Familial LCAT deficiency include:

While there is no definitive medical therapy to treat LCAT deficiency, the following methods can help mitigate complications and alleviate symptoms:

Surgery

  • Patients dependent on hemodialysis with worsening renal function are indicated for renal transplant.
    • Lipid abnormalities usually recur after a renal transplant .[31]

Prevention

  • There are no screening recommendations for the disease. Patients are advised regular follow up, medication compliance and monitoring of the renal function to prevent progressive decline in renal function.

References

  1. 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.
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