HomeHealth articlesgenetic disorderWhat Causes a Lack of Lecithin Cholesterol Acyltransferase?

Lecithin Cholesterol Acyltransferase Deficiency - Causes, Symptoms, Pathophysiology, Treatment

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Lecithin cholesterol acyltransferase is crucial for synthesizing cholesteryl esters in plasma, encouraging high-density lipoprotein production.

Written by

Dr. Palak Jain

Medically reviewed by

Dr. Vedprakash Verma

Published At February 3, 2023
Reviewed AtFebruary 3, 2023

Introduction

The lipoprotein-associated enzyme lecithin cholesterol acyltransferase (LCAT) is essential for the maturation of high-density lipoprotein (HDL) particles, the esterification of free cholesterol, and the intravascular stage of reverse cholesterol transport. In plasma, lecithin cholesterol acyltransferase is an enzyme linked to low-density lipoproteins and high-density lipoproteins.

The following are the steps that lecithin cholesterol acyltransferase catalyzes for the production of cholesterol esters in lipoproteins:

The addition of unesterified cholesterol and phosphatidylcholine equals the addition of cholesterol ester and lysophosphatidylcholine.

Fish eye disease and familial full lecithin cholesterol acyltransferase deficiency are the two kinds of lecithin cholesterol acyltransferase deficiency that run in families (partial LCAT deficiency).

What Causes a Lack of LCAT?

Lecithin cholesterol acyltransferase deficiency results from inadequate or absent catalytic activity of the Lecithin cholesterol acyltransferase deficiency enzyme, encoded by the lecithin cholesterol acyltransferase gene and catalyzes the synthesis of cholesterol esters in lipoproteins (16q22.1). The clinical manifestations are believed to be caused by an accumulation of unesterified cholesterol in the body, such as in the kidneys, erythrocytes, and cornea. The lecithin cholesterol acyltransferase gene has had more than 85 mutations found so far. Lecithin cholesterol acyltransferase deficiency is inherited in an autosomal recessive manner.

What Are the Different Forms of LCAT?

1. The family form

Lecithin cholesterol acyltransferase activity toward high-density lipoprotein and low-density lipoproteins is absent in familial lecithin cholesterol acyltransferase deficiency, a condition originally identified in a Norwegian family in 1967.

2. Fish eye form

Lecithin cholesterol acyltransferase activity only against high-density lipoprotein is absent in fish eye disease, a condition first identified in two families of Swedish ancestry.

What Are the Signs and Symptoms of Different Forms of LCAT?

1. The family form's symptoms include

  • Kidney failure.

  • Hemolytic anemia in target cells.

  • Diffuse corneal opacities that impede vision.

Less frequent signs and symptoms include

2. Fish-eye form’s symptoms include:

  • The eye's cornea was so opaque or foggy with cholesterol flecks that it resembled a boiled fish.

Less frequent signs and symptoms include

  • Atherosclerosis.

  • Hepatomegaly (swollen liver).

  • Splenomegaly (enlarged spleen).

  • Enlarged lymph nodes.

Most of the time, symptoms are absent in people with only one copy of the mutant gene.

What Is the Pathophysiology Behind LCAT?

When lecithin cholesterol acyltransferase is lacking, unesterified cholesterol builds up in several bodily tissues. Esters of cholesterol, carried in high-density lipoprotein, are effluxed from cells as free cholesterol. The lecithin cholesterol acyltransferase enzyme converts free cholesterol on high-density lipoprotein to cholesterol ester, allowing high-density lipoprotein to mature. Apolipoprotein A1 and Apolipoprotein A2 in the blood are rapidly broken down by high-density lipoprotein due to the lack of lecithin cholesterol acyltransferase, which prevents high-density lipoprotein from maturing. Like nascent high-density lipoprotein, the surviving form of high-density lipoprotein looks.

The liver secretes the lecithin cholesterol acyltransferase glycoprotein, which makes lysophosphatidylcholine and cholesterol ester before binding to lipoproteins. Normal production of the enzyme is necessary for the metabolism of high-density lipoproteins. However, in fish-eye sickness, the enzyme cannot esterify or convert the acid in cholesterol in high-density lipoprotein particles into an alkyl. The enzyme is still working on the cholesterol molecules in low-density lipoproteins and very low-density lipoproteins. Thus there is only a partial deficit of low-density lipoproteins. The lipid buildup on the cornea is what gives eyes their opaqueness.

One of the enzymes responsible for preserving cholesterol homeostasis is lecithin-cholesterol acyltransferase. In familial lecithin cholesterol acyltransferase deficiency, irregular lipid deposition results in nephrotic syndrome and renal damage and frequently progresses to end-stage renal disease.

For familial lecithin cholesterol acyltransferase deficiency patients, renal dysfunction is the leading cause of morbidity and mortality. Proteinuria is the primary early sign of kidney illness. By the fourth and fifth decades of life, the condition becomes more severe and frequently progresses to nephrotic syndrome and end-stage renal disease.

According to light microscopy:

  • The walls of the glomerular capillaries have thickened.

  • The basement membrane of glomerular capillary walls has an erratic bubble appearance.

  • Variable foam cells infiltrate the capillaries and mesangial areas, causing the mesangium (a thin membrane that supports the capillaries surrounding the tubule of a nephron) to swell, frequently giving the appearance of a bubble.

How Does LCAT Impact the Reverse Transfer of Cholesterol?

To maintain the gradient of unesterified cholesterol between the cell membrane and extracellular acceptors, the initial and rate-limiting step in reverse cholesterol transport, lecithin cholesterol acyltransferase, is essential. According to the reverse cholesterol transport theory, high-density lipoprotein removes cholesterol from foam cells and transfers it to the liver with its main apolipoprotein, apoA-I. Due to divergent results between animal models and humans, the role of lecithin cholesterol acyltransferase in reverse cholesterol transport has grown contentious. Although a significant reverse cholesterol transport impairment might be anticipated, neither lecithin cholesterol acyltransferase-deficient humans nor mice do not seem to have a noticeably higher risk of atherosclerosis. It may be predicted that there was a significant flaw in reverse cholesterol transport. Many foam cells in the glomeruli vanished after the patient's lecithin cholesterol acyltransferase activity returned to normal, indicating that lecithin cholesterol acyltransferase is essential for reverse cholesterol transport, at least for the elimination of foam cells from the glomeruli.

What Are Treatment Options to Treat LCAT?

Therapy is concentrated on symptom management because there is currently no specific medication to treat lecithin cholesterol acyltransferase deficiency. Corneal transplantation may be an option for patients with severe vision impairment brought on by cholesterol corneal opacities. For patients with kidney failure, dialysis or kidney transplantation may be necessary. Albeit, it has been shown that the condition recurs in the transplanted organ. In a short-term trial, plasma infusions enhanced lipid profiles; however, their long-term advantages have yet to be proven. Recently, it was demonstrated that certain lysosomal illnesses could be treated with enzyme replacement treatment. Lecithin cholesterol acyltransferase functions throughout the plasma compartment without organ-specific distribution, making familial lecithin cholesterol acyltransferase deficiency a promising option for enzyme replacement treatment. Human recombinant lecithin cholesterol acyltransferase therapy quickly restored the typical lipoprotein profile in lecithin cholesterol acyltransferase-knockout mice and boosted cholesterol efflux in mouse models of lecithin cholesterol acyltransferase deficiency. The development of an enzyme replacement therapy for human congenital lecithin cholesterol acyltransferase efficiency is ongoing.

Conclusion:

Lecithin cholesterol acyltransferase mutations interfere with cholesterol esterification, preventing the formation of mature high-density lipoprotein particles. This is associated with apoA-I catabolism. The amount of free circulating cholesterol in the bloodstream rises dramatically, resulting in corneal opacities and high-density lipoprotein-C levels of 10 mg/dL. "Fish-eye" disease refers to partial lecithin cholesterol acyltransferase deficiency. Early in adulthood, complete deficiency results in hemolytic anemia and progressive renal insufficiency. It is not believed that this rare disease causes premature atherosclerosis. The demonstration of decreased cholesterol esterification in the plasma serves as laboratory confirmation.

Mutations cause almost all cases of familial lecithin cholesterol acyltransferase deficiency in the structural lecithin cholesterol acyltransferase gene. A specific gene region has been found to contain several mutations that cause fish eye disorder. Because there is no specific treatment for lecithin cholesterol acyltransferase deficiency, therapy focuses on symptom relief.

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Dr. Vedprakash Verma
Dr. Vedprakash Verma

General Practitioner

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