Phosphatidylcholine-cholesterol acyltransferase deficiency

Introduction to phosphatidylcholine-cholesterol acyltransferase deficiency In 1967 and 1968, Gjone and Norum first reported a familial disease characterized by proteinuria, anemia, hyperlipidemia, and corneal opacity. Further studies have found that patients have elevated plasma cholesterol and triglyceride levels, hemolytic eggs. Phospholipid levels are reduced, free cholesterol phosphatidylcholine levels are increased, often involving the kidneys, and renal failure is the cause of death. basic knowledge The proportion of illness: 0.002% Susceptible people: no special people Mode of infection: non-infectious Complications: atherosclerosis, hypertension, renal failure

Phosphocholine-cholesterol acyltransferase deficiency cause

(1) Causes of the disease

The disease is autosomal recessive. The gene encoding phosphatidylcholine-cholesterol acyltransferase is linked to the gene encoding -binding globin. It is located on the long arm of chromosome 16, and Gjone et al. confirmed four families from Norway. The disease is due to a genetic mutation, and Teisberg and Gjone estimate the frequency of the gene to be 2%.

The amount and activity of plasma phosphatidylcholine-cholesterol acyltransferase are different between different homozygous families and different heterozygous families, suggesting that the disease has different gene expression, and some Norwegian homozygous patients plasma phosphatidylcholine - The amount of cholesterol acyltransferase is 10% to 20% of normal, while Sardinia is 5% to 10% of normal people. There is also a Canadian that cannot detect phosphatidylcholine-cholesterol acyltransferase in plasma. family.

(two) pathogenesis

The human phosphatidylcholine-cholesterol acyltransferase gene is located on chromosome 16, the gene series has been determined, and the cDNA has been successfully cloned. At the molecular level, the pathogenesis of phosphatidylcholine-cholesterol acyltransferase deficiency is heterogeneous. It is suggested that the mutations in most affected family genes are independent. The structural defect of an Italian patient is due to exon mutation. In three Japanese patients, two amino acid substitutions are caused by different single nucleotide translocations. Three patients were inserted between arginine and alanine due to insertion of 3 base pairs. For some families, cDNA cloning and restriction fragment length polymorphism analysis did not reveal gene rearrangement. No abnormal fragment was found. In a patient with partial phosphatidylcholine-cholesterol acyltransferase deficiency (fisheye disease) associated with high-density lipoprotein, the gene sequence of phosphatidylcholine-cholesterol acyltransferase was normal, but Apo The protein A-2 gene has been mutated.

Renal damage may be the result of deposition of various lipid components inside and outside the glomerular cells. Proteinuria may be caused by damage to the glomerular basement membrane due to lipid swallowing and dense membrane-like structures, in arteries and arterioles. Continued lipid deposition may cause endothelial cell detachment and necrosis, causing progressive glomerular sclerosis and impaired renal function.

Electron microscopy showed that the patient's plasma very low-density lipoprotein abnormalities were 60 nm notched abnormal particles, and there were three main manifestations of low-density lipoprotein abnormalities:

1.90 nm large particles having a layered structure.

2.30 ~ 80nm dish-shaped particles.

3. 20 ~ 22nm spherical particles.

High-density lipoprotein abnormalities appear as discs or globules with a diameter of about 6 nm. It is likely that these abnormal lipids are deposited in various affected tissues, and/or are digested by phagocytic cells, eventually forming microscopic "foam cells" and "Sea blue tissue cells", it is believed that low molecular weight low density lipoprotein is extremely important in the pathogenesis, and may cause glomerular damage due to its deposition.

Phosphatidylcholine-cholesterol acyltransferase deficiency prevention

The disease is an autosomal recessive hereditary disease and there are no effective preventive measures at present. Maternal women do a good job of prenatal care to avoid the birth of such children.

Phosphocholine-cholesterol acyltransferase deficiency complications Complications atherosclerosis hypertension renal failure

Patients with multiple diseases complicated with corneal opacity or retinal artery dilatation bleeding in young patients may also have atherosclerosis and hypertension, and severe cases may be complicated by renal failure.

Phosphatidylcholine-cholesterol acyltransferase deficiency symptoms common symptoms triad corneal opacity erythrocytosis retinal hemorrhage hypertension renal damage atherosclerosis

This family is a family of autosomal recessive hereditary diseases, mainly characterized by anemia, corneal opacity and nephrotic syndrome triad. The clinical manifestations of all cases reported in the world are similar.

1. Kidney performance

Renal damage is common in the family of hereditary phosphatidylcholine-cholesterol acyltransferase deficiency. In most patients, proteinuria (0.5-1.5 g/24h) in the range of non-renal disease occurs in early years, mainly by albumin and a small amount of 1- and 2 balls. Protein composition, urine test can be completely normal or a small amount of red blood cell cast, transparent tube and granular tube type, in the 31 to 49 years old, increased proteinuria severity, often manifested as obvious symptoms of kidney disease, many patients are often misdiagnosed For chronic glomerulonephritis, kidney disease is often accompanied by high blood pressure and rapid loss of renal function, especially in end-stage renal disease.

2. Extrarenal performance

Mild anemia is common and characterized by target shape, abnormal shape and reticular erythrocytosis. Red blood cell survival is reduced, osmotic fragility is reduced, and slight increase in indirect bilirubin concentration in blood supports the presence of mild hemolysis. Red blood cell damage is due to red blood cells. Membrane lipid and lipoprotein components are disordered, including increased non-esterified cholesterol, reduced acetylcholinesterase, decreased sphingomyelin, and increased cholesterol phospholipid ratio.

Corneal opacity occurs in all patients at a young age. Lipid arches and gray spots cover the corneal stroma. This may be the manifestation of extracellular lipid inclusions. Most of the visual sensitivity is not impaired. A few patients have dilated arteries. Retinal hemorrhage can be seen. In patients with this disease, atherosclerosis is accelerated, and the esterified cholesterol in atheroma is less than that in patients with normal arteriosclerosis with phosphatidylcholine-cholesterol acyltransferase.

Examination of phosphatidylcholine-cholesterol acyltransferase deficiency

The blood test mainly has abnormal phosphatidylcholine-cholesterol acyltransferase. In some patients, the enzyme is completely absent. In some patients, the enzyme function is reduced, and some patients show a decrease in the amount of enzyme. Therefore, radiation is required for patients with this disease. The amount of plasma phosphatidylcholine-cholesterol acyltransferase is determined by immunoassay and its activity should also be determined. The level of heterozygous phosphatidylcholine-cholesterol acyltransferase is between normal level or homozygote, low plasma. The level of phosphatidylcholine-cholesterol acyltransferase has no characteristic diagnostic significance. The level of this enzyme is lower in women than in women, and the smoker is lower than non-smokers. In a few patients with hepatorenal syndrome, the enzyme activity is lower than that of normal people.

Patients with abnormal plasma lipids and lipoproteins, many patients with fasting plasma turbidity, total cholesterol levels are significantly different between families, normal or increased, free cholesterol and phosphatidylcholine levels increased, cholesterol ester and lysolecithin concentrations decreased Plasma triacylglycerol levels are often elevated, high-density lipoprotein cholesterol levels are usually reduced, patients with high-density lipoproteins have two subclasses, the first subclass has a large molecular weight, which acts as an 2-globulin in electrophoresis, and patients with liver disease. High-density lipoprotein is similar and partially homologous; another subclass has a small molecular weight. After gel filtration, patients with low-density lipoprotein are divided into three sub-categories. The first sub-class is mainly composed of phosphatidylcholine and non-ester. Cholesterol composition; second subclass is similar to lipoprotein X, which was once considered to be characteristic of cholesterol-induced liver disease; third subclass is similar to normal low-density lipoprotein, but there will be more triacylglycerol, lower in patients The abnormal part of density lipoprotein is called LM-LDL, and it is considered that this part of LDL is nephrotoxic.

The variant of this disease (fish eye disease) is characterized by corneal opacity and dyslipoproteinemia, which is associated with impaired high-density lipoprotein esterification, and its acylation of low-density lipoprotein cholesterol or very low-density lipoprotein cholesterol is normal. It has been suggested that the phosphatidylcholine-cholesterol acyltransferase deficiency in these fisheye patients is limited to enzymes that acylate high-density lipoproteins (-phosphatidylcholine-cholesterol acyltransferase), while Lipoproteins are not related to the esterification of very low-density lipoproteins (-phosphatidylcholine-cholesterol acyltransferase), and patients with fisheye diseases and those with classic phosphatidylcholine-cholesterol acyltransferase deficiency have been further proposed. In contrast, both - and -phosphatidylcholine-cholesterol acyltransferase activities are reduced.

Renal biopsy

(1) Light microscopy: The glomerular involvement is most obvious. It can be seen that the capillary wall is thickened, the basement membrane is irregular, and there are often translucent bands or vesicles. Sometimes the double-contoured wall is visible, and the mesangial area is widened. The light-stained band can be seen, and the vesicles can be seen in the matrix to make it have a honeycomb appearance. In most patients, a number of foam cells can be found in the capillary lumen, and similarities can be found in the interstitial tissues, arteries and arterioles. Cells, in the glomerular capillary lumen and mesangium, can be seen as "marine blue tissue cells" lipid-containing cells, with the progression of glomerular lesions, can be complicated by segmental sclerosis and plasma protein deposition, Magil When oil red "O" staining was found, there was a large amount of "lipid droplets" in the glomerulus, and Stokkek et al. stained the frozen sections with oil red "O", and stained lipid deposits were observed under the small arterial endothelium.

(2) Immunofluorescence: A typical feature of immunofluorescence microscopy is that all immunoglobulins and complement components are negative, so kidney damage is not supported by immune mediated, but is reported individually in the glomerular capillary wall and (or Immune globulin and/or complement were weakly positive in the mesangial area. Unfortunately, immunofluorescence was not performed in patients with ionic deposition of electron dense deposits in the literature.

(3) Ultrastructural features: Ultrastructural abnormalities are very obvious, the mesangial matrix and basement membrane are penetrated by transparent bands (cavities), and the transparent bands have small circular dense structures or lamellar appearances. It is a "membrane-wrapped body" composed of membranes. In the capillary wall, these structures may be located under the endothelium, in the basement membrane or under the epithelium. These special structures may also be located in the basement membrane of the Baumannian capsule and the renal tubule, arteries and small Arterial subendothelial and interstitial tissues, but both in the extracellular part, glomerular endothelial cells are occasionally isolated or missing. With the above changes, dense large particles and membrane-like substances in the lumen can also be seen. "Sea blue tissue cells" exist.

There are other ultrastructure "sediments", including densely stained striped fibril aggregates and fine-grained electron-dense substances, distributed throughout the capillaries, mainly under the epithelium, and mesangial matrix, another type The sediment consists of a clustered circular or layered dense structure. These three ultrastructural deposits are often present in the same segment of the glomerulus, or they can exist alone. Lager et al. studied the same patient with repeated kidneys for 8 years. Biopsy results showed that the cross-striped fibrils and layered dense structures decreased at the second renal biopsy, while the dense granules and membrane-like translucent areas increased. In the early biopsy specimens, the sediments were mainly under the epithelium; In the specimen, the sediment is mainly in the mesangial area and under the endothelium.

The pedicle of the glomerular visceral epithelial cells disappeared extensively. When focal sclerosis occurred, the cells formed thick vacuoles and dense lysosome inclusions.

Renal damage also occurs again 6 months after or after cadaveric kidney transplantation. Foam cells are irregularly distributed in glomerular capillaries and arterial intima, frozen sections stained with oil red, and ultrastructural studies show small in kidney There is an extracellular lipid structure present in the basement membrane and mesangial matrix.

2. Other histopathological examination Non-renal tissue may also have intracellular and extracellular lipid inclusions, but the degree is not as significant as the kidney. The aorta, renal artery, and tibia have been found to surround the granular lipids, sometimes visible in foam. In the cells, there are aggregated membrane-enclosed particles around the blood vessels in the liver. There are large and irregular cytoplasmic myelin bodies in the Kupffer cells. There are round lipid droplets in the liver cells, and the spleen is extracted. There are large aquamarine tissue cells in the biopsy specimens, and the cytoplasm is filled with dense multi-layered membranes (myelin-like bodies), which are presumed to be phagocytic non-esterified cholesterol and phosphatidylcholines. Alkali, similar abnormal cells are found in other reticuloendothelial structures such as lymph nodes. The outer cell membrane of the spleen sinus is surrounded by particles, and the cell outer tissue is also visible in the ocular tissue (membrane-wound particles).

Abnormal red blood cell morphology, increased "target cells" in bone marrow smears and peripheral blood, abnormal red blood cell structure may be related to abnormal lipid components of cell membrane.

Diagnostic identification of phosphatidylcholine-cholesterol acyltransferase

Diagnostic criteria

Clinical anemia, corneal opacity and nephrotic syndrome triad, suggesting the diagnosis of this disease, but need to be differentiated from liver disease, especially cirrhosis with kidney disease, a variety of causes can lead to a variety of immune-mediated In glomerulonephritis, the extracellular lipid membrane is also surrounded by granules in the basement membrane and mesangial matrix, but it is often located in the vicinity of electron-dense deposits. Compared with patients with this disease, the number is small and the distribution is limited. Other identification points Including the history of liver disease, family history and laboratory results, and to carefully observe the characteristics of renal tissue immunofluorescence and light microscopy, cirrhosis with kidney disease, kidney biopsy will find immunoglobulin and complement in glomerular deposition, IgA is often deposited on the mesangial or capillary wall. There may be an increase in mesangial cells, an enlarged vascular plexus, and a double-layered contour of the capillary wall. It can be seen that the epithelial "nail spike" is formed, and foam cells are rare. In addition, clinically Other features of liver disease complicated with kidney disease can be found.

Differential diagnosis

1. Must be differentiated from liver disease, especially cirrhosis with kidney disease.

2. Different from chronic glomerulonephritis, many patients are often misdiagnosed as chronic glomerulonephritis, and should also be distinguished.

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