Lecithin cholesterol acyltransferase deficiency

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 accumalation of free cholesterol in the cornea,RBC membrane and kidney causing symptoms. Based on the type and location of the mutation it is classified into complete enzyme deficiency(Familial LCAT deficiency) and incomplete enzyme deficiency(Fish Eye Disease). Patients have low HDL C levels which is the characteristic finding.

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 .
• 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.
• 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.
• 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 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 but patients with complete or partial LCAT deficiency had no significant difference in risk of developing atherosclerosis when compared to heterozygous carriers of the same mutation.

Pathophysiology

Pathogenesis

LCAT Function

• Majority of the enzyme is associated with HDL C, very small amount with LDL C.

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

• LCAT helps in reverse cholesterol transport by:
  • 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 , which are implicated in the development of glomerulopathy .

Genetics

• Autosomal Recessive inheritance, monogenic disorder.
• LCAT gene is on chromosome 16, multiple mutation sites are identified.
• Expression of clinical features and severity of disease in homozygous patients depends on the type and locus of the mutation.
• Heterozygous patients have a intermediate biochemical expression with .

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.
• Sea blue histiocytes on Wright-Giemsa are seen in bone marrow and spleen.

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:

• 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.

	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 Low Apo A1 and Apo A2 Elevated Apo E and Triglycerides Low LDL C	Elevated free cholesterol HDL C < 27 mg/dL Low Apo A1 and 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

Diagnosis

History and Symptoms

• The most common clinical manifestaions in FLD include annular corneal opacity, hemolytic anemia and renal disease.
• 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.
• Hemolytic anemia : Excess free cholesterol and phospholipid deposition and increased phosphotidylcholine in the RBC membrane causes erythrocyte fragility. 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
• 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.
• 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:
  • Homozygotes have apoA-I in plasma present only in preβ-1 and α-4 discoidal HDL particles.
  • Heterozygotes for LCAT deficiency have less than 50% of normal large a-1 HDL, but two-fold increases in very small β 1 HDL.
  • Elevations in free cholesterol-enriched VLDL, which 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, but it is in the process of manufacture.
• High dose angiotensin receptor blockers help in improving the blood pressure, proteinuria and kidney function.

Surgical Therapy

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