Lecithin cholesterol acyltransferase deficiency
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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,but the risk of developing atherosclerosis and cardiovascular disease in LCAT deficiency is still not well defined and is controversial.

# Historical Perspective
- 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. 
- 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.
- In 1967, Norum and Gjone reported 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. Other additional findings included were :
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.
- 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.
- 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. 

# 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:
- 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.

# Pathophysiology

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

### LCAT Function
- Majority of the enzyme is associated with HDL C; only a very minor amount is associated with LDL C.
- LCAT helps in reverse cholesterol transport by:
Cholesterol esters are hydrophobic and occupy the core of the lipoprotien preventing backflow of cholesterol back into the cells.
Promoting unidirectional efflux of free cholesterol from the cells via ABCA1 and scavenger receptor type B-I (SR-BI) by creating a concentration gradient.
- Cholesterol esters are hydrophobic and occupy the core of the lipoprotien preventing backflow of cholesterol back into the cells.
- 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

## Genetics
LCAT deficiency presents the following genetic characteristics:
- LCAT deficiency is transmitted in a autosomal recessive inheritance.
- LCAT gene is located on chromosome 16, and multiple mutation sites have been identified.
- The expression of clinical features and severity of disease in homozygous patients is determined by the type and locus of the mutation.
- Heterozygous patients have an intermediate biochemical expression with reduced plasma HDLC and Apo A1 levels.

## 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 (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.
- 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.
- Sea blue histiocytes on Wright-Giemsa are observed in bone marrow and spleen.

# 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.
- 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 senilis which is different from Tangier disease where it is more central and dense.Visual disturbances are not common.
- Hemolytic anemia results from excessive free cholesterol, phospholipid deposition, and increased phosphotidylcholine in the RBC membrane causing erythrocyte fragility.
- 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. 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
- 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 
- 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.
- 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.
- 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:
- Homozygotes have Apo A1 in plasma present only in pre-1 and -4 discoidal HDL particles after Apo A1 immunoblotting.
- 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 LDLhCaving  betanmobility stead of pre  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.

# Low HDL C differential diagnosis

# 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. 
Currently it is at the manufacturing stage and is not yet available for widespread use.
- 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.

## Surgery
- Patients dependent on hemodialysis with worsening renal function are indicated for renal transplant.
Lipid abnormalities usually recur after a renal transplant .
- Lipid abnormalities usually recur after a renal transplant .

# 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.