RU2637412C1 - Method for determination of atherosclerotic damage of vascular wall in patients with abdominal obesity and nonalcoloral fat liver disease (versions) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: in vitro diagnostics of pathological changes in the Steatoscreen liver is performed and the value of Steatoscreen is determined. At that, the average thickness of the intima-media of the carotid artery Y in the patient is determined by the formula Y=0.64+0.34 Steatoscreen, and if Y≥0.86 mm, the patient is diagnosed with early signs of atherosclerosis. A method for diagnosis using a peak systolic blood flow velocity in the internal carotid artery is also proposed.

EFFECT: diagnosis of liver pathology and development of atherosclerotic lesion of the vascular wall without application of invasive techniques.

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Description

The invention relates to medicine and can be used to determine atherosclerotic lesions of the vascular wall in patients with pathological changes in the liver parenchyma with non-alcoholic fatty liver disease.

To date, there is a clear idea of atherosclerosis as a multifocal disease, which is based on complex disorders in biochemical, immunological and molecular genetic processes. Atherogenesis involves a complex set of interactions between the vascular wall, blood cells, biologically active substances dissolved in it, and local blood flow disturbance (R. Virkhov’s triad). As a result of atherosclerosis, there is a gradual local stenosis of the coronary, brain and other arteries due to the formation and growth of atherosclerotic plaques in them.

The pathogenesis of atherosclerosis is a multifactorial and dynamic process. To date, there is no comprehensive theory to explain and take into account all its aspects. Today, two hypotheses of the development and formation of atherosclerosis dominate: the “response to damage” hypothesis and the lipid-infiltration hypothesis, which in principle do not contradict and largely complement one another in explaining the various processes observed in atherosclerosis.

Today, much attention is paid to the study of the role of non-alcoholic fatty liver disease (NAFLD) in the development of atherosclerosis.

H1,2. Diagnosis of non-alcoholic fatty liver disease (NAFLD), Diabetologia. 2016 Apr 18].It has been shown that in the liver with fatty hepatosis, the breakdown of insulin and glucose utilization are violated, the conditions for the synthesis of atherogenic fractions of cholesterol and triglycerides (TG) are created, which contributes to the development of disorders of carbohydrate and lipid metabolism, the early appearance of atherosclerosis and related cardiovascular diseases [

H1.2. Diagnosis of non-alcoholic fatty liver disease (NAFLD), Diabetologia. 2016 Apr 18].

NAFLD leads to the development of non-alcoholic steatohepatitis (NASH), which itself can induce a fibrogenic reaction, which can lead to the development of cirrhosis [Day CP. Best Pract. Res. Clin. Gastroenterol. 2002; 16: 663-78].

Being involved in the pathological process, the liver becomes not only a target organ, but also itself enhances metabolic disorders. The clinical significance of metabolic disorders in NAFLD is high. Their combination greatly accelerates the development and progression of atherosclerosis and related cardiovascular diseases.

Correlation relationships were found between the severity of pathological changes in the liver and changes in the thickness of the intima / media of the carotid arteries, the severity of coronary atherosclerosis, calcification of the aortic valve and endothelial dysfunction. A high incidence of coronary atherosclerosis in patients with NAFLD has been established. A meta-analysis of seven studies involving about 3,500 people showed that NAFLD, diagnosed by ultrasound, is highly correlated with an increase in carotid intima-media thickness and an increase in the prevalence of atherosclerotic plaques [Sookoian S., Pirola C.J. // J. Hepatol. - 2008. - No. 49. - P. 600-607, Sinn DH1, Cho SJ, Gwak GY, Cho J, Gu S, Seong D, Kang D, Kim H, Yi BK, Paik SW. 100. Medicine (Baltimore). 2016 Jan; 95 (3): e2578 Doi: 10.1097 / MD Nonalcoholic Fatty Liver Disease for Identification of Preclinical Carotid Atherosclerosis., Sookoian S., Pirola C.J. // J. Hepatol. - 2008. - No. 49. - P. 600-607].

In this regard, the study of NAFLD as an independent, independent additional risk factor for the development of atherosclerosis [Identification of Preclinical Carotid Atherosclerosis. 25. Sookoian S., Pirola C.J. // J. Hepatol. - 2008. - No. 49. - P. 600-607].

The work of Targher G. (2006) is known, in which it was shown that changes in the thickness of the carotid artery intima-media (TCIM OCA) occur already in the early stages of histologically verified liver steatosis and progress as the histological manifestations of NAFLD become more severe, regardless of classical factors of cardiac vascular risk, insulin resistance and other components of the metabolic syndrome (MS). [Targher G., Bertolini L., Padovani R., et al. // Diabetes Care. - 2004. - No. 27. - P. 2498-2500. Relations Between Carotid Artery Wall Thickness and Liver Histology in Subjects With Nonalcoholic Fatty Liver Disease. Targher G., Bertolini L., Padovani R., et al. // Diabetes Care. - 2006. - No. 29. - P. 1325-1330. Targher G., Arcaro G. // Atherosclerosis. - 2007. - No. 19. - P. 235-24039]. The study included 85 outpatients with NAFLD. All patients with chronically elevated liver enzymes and steatosis diagnosed by ultrasound. To determine pathological changes in the liver, a puncture biopsy of the liver and histological classification of Brant were used. The control group consisted of 160 healthy volunteers.

TCIM OCA was measured by ultrasound in three measurements near the bifurcation of the common carotid artery. Then all readings were averaged. In patients with NAFLD, TCIM OCA was significantly greater than TCIM of the carotid arteries of the control group. Patients with NAFLD had a greater number of atherosclerotic plaques (69.1 versus 34.2%, p <0.001) compared with the control group.

It is important to note that the severity of histological signs of NAFLD (steatosis and fibrosis) with high reliability correlates with an increase in TCIM of the carotid arteries.

Targher G. was shown for the first time that, firstly, in patients with NAFLD diagnosed by puncture biopsy, the thickness of TCIM OCA is significantly greater compared to the control group, and secondly, the severity of histological changes in NAFLD independently predicts the severity atherosclerotic lesions of the vascular wall of the carotid arteries.

The results of this study confirm the hypothesis that the severity of histological changes in NAFLD is closely associated with early carotid arteriosclerosis. However, the disadvantage of this work is that the authors use a biopsy as an examination tool, which leads to an increase in the cost of analysis, a deterioration in patient adherence to the examination and possible complications.

Another well-known method of non-invasive diagnosis of pathological changes in the liver is Elastography. Elastography is a study of liver tissue that is performed using the FibroScan apparatus. The principle of elastography is based on the relationship between tissue elasticity and the degree of fibrosis: the lower the elasticity (that is, the denser the liver tissue), the more pronounced fibrosis. Fibroscanning of the liver has the following disadvantages: it is impossible to assess necrotic changes in tissues, poor sensitivity in the early stages of fibrosis, distortion of the result in overweight patients with an acute inflammatory process in the liver.

A widely known and often used method for diagnosing pathological changes in the liver is an ultrasound scan of the liver. This is a non-invasive instrumental method based on the determination of four ultrasound features: attenuation of the echo signal, diffuse hyperechoogenicity of the liver, increased echogenicity of the liver compared with the kidneys and vague vascular pattern.

The disadvantages of this method are the complex reproducibility, the ambiguity of the interpretation of the obtained data, the difficulty of fixing the results to assess the dynamics of changes, as well as a decrease in the sensitivity of the method with an increase in the amount of visceral fat.

For screening diagnosis of pathological changes in the liver in 2007, non-invasive bioprognostic tests were approved:

Steatoscrin, Fibrotest (FT) and Fibromax (FM) (Biopredictive, Paris France, US Pat. No. 6,631,330) used as a replacement marker for chronic hepatitis C [Poynard T, et al. Comp Hepatol. 2004; 3: 8] and B [Myers RP, et al. J Hepatol. 2003; 39: 222-30] and, more recently, for alcoholic liver disease [Callewaert N, et al. Nature Med 2004; 10; 1-6; Naveau S, et al. Clin Gastroenterol Hepatol].

The basis of the invention is the task of developing a method for diagnosing signs of early atherosclerotic vascular wall lesions in patients with NAFLD based on ultrasound diagnostics of the average thickness of the intima-media of the carotid artery and peak systolic blood flow velocity in the internal carotid artery, which would provide predictive detection of pathological changes in vessels in patients with various pathological changes in the liver with NAFLD, which would be reliable enough for zheniya need for liver biopsy.

The solution to this problem is provided by the fact that in the method for determining atherosclerotic lesions of the vascular wall in patients with abdominal obesity and non-alcoholic fatty liver disease, including in vitro diagnosis of pathological changes in the liver, Steatoscrin and determination of the value of Steatoscrin, the average thickness of the intima-media of the carotid artery in a patient is determined according to the formula

Y = 0.64 + 0.34 Steatoscrin,

and if Y≥0.86 mm, then the patient determines the early signs of atherosclerosis.

In the second embodiment, the solution of the problem is ensured by the fact that in the method for determining atherosclerotic lesions of the vascular wall in patients with abdominal obesity and non-alcoholic fatty liver disease, including in vitro diagnosis of pathological changes in the liver, Steatoscrine and determination of the value of Steatoscrin, peak systolic blood flow velocity in the internal carotid artery The patient is determined by the formula

Y = -1.52 + 3.785 Steatoscrin,

and if Y≥110 cm / s, then the patient determines the early signs of atherosclerosis.

The present invention provides a diagnostic method that prospectively determines the value of pathological changes in the liver diagnosed using the non-invasive Steatoscrin method to determine the likely atherosclerotic lesion of the vascular wall, with reliability sufficient to reduce the likelihood of a liver biopsy and screening studies of brachiocephalic arteries.

This can be useful for patients and society in order to reduce the risk of liver biopsy, and also reduces the cost of the analysis and does not lead to possible complications from a biopsy.

The invention is illustrated using FIG. 1-5.

In FIG. Figure 1 shows the average TCIM OCA in all groups, where S1, S2, S3, S4 are the levels of severity of pathological changes in the liver according to the Steatoscreen scale: steatosis is not diagnosed, severe steatosis, fibrosis, steatofibrosis, respectively. In FIG. Figure 2 shows the values of TCIM OCA in patients with more severe pathological changes in the liver parenchyma, where S2, S3, S4 are the levels of severity of pathological changes in the liver according to the Steatoscrin scale: steatosis is not diagnosed, severe steatosis, fibrosis, steatofibrosis, respectively. In FIG. Figure 3 shows the values of TCIM OCA in patients with atherosclerotic plaques, where S2, S3, S4 are the levels of severity of pathological changes in the liver according to the Steatoscrin scale: steatosis is not diagnosed, severe steatosis, fibrosis, steatofibrosis, respectively. In FIG. Figure 4 shows the relationship between pathological changes in the liver tissue and the degree of thickening of CMM OCA. In FIG. Figure 5 shows the dependence of the degree of thickening of CMM OCA on the severity of pathological changes in the liver, diagnosed using a non-invasive bioprognostic test - Steatoscrin. In FIG. Figure 6 shows the average values of the average systolic velocity in OCA and the peak systolic velocity in the ICA in all groups, where S1, S2, S3, S4 are the levels of severity of pathological changes in the liver according to the Steatoscrin scale: steatosis is not diagnosed, severe steatosis, fibrosis, steatofibrosis, respectively. Ck Wed OCA - average systolic velocity in the common carotid artery, sc. Peak. syst. ICA is the peak systolic velocity in the internal carotid artery. In FIG. Figure 7 shows blood flow velocity indices in OCA and ICA in patients with NAFLD and more severe pathological changes in the liver, where S2, S3, S4 are the levels of severity of pathological changes in the liver according to the Steatoscrin scale: steatosis is not diagnosed, severe steatosis, fibrosis, steatofibrosis, respectively. Ck Wed OCA - average systolic velocity in the common carotid artery, sc. Peak. syst. ICA is the peak systolic velocity in the internal carotid artery. In FIG. Figure 8 shows the relationship of speed indicators of blood flow in the carotid arteries with the severity of pathological changes in the liver. In FIG. Figure 9 shows a diagram illustrating the presence of atherosclerotic plaques according to USG data in patients with various levels of pathological changes in the liver, where S2, S3, S4 are the levels of severity of pathological changes in the liver according to the Steatoscrin scale: steatosis is not diagnosed, severe steatosis, fibrosis, steatofibrosis, respectively. In FIG. Figure 10 shows the dependence of the peak systolic blood flow velocity in the ICA on the severity of pathological changes in the liver, diagnosed using a non-invasive bioprognostic test - Steatoscrin.

In an ultrasound study of carotid arteries, TCIM OCA was measured according to a standard method on a Voluson 730 Expert. Apparatus equipped with a linear sensor with a phased array with a frequency of 7.5 MHz. The thickness of the CMM OCA was measured at 3 points 1 cm below the level of bifurcation on the right and left. The average TCIM OSA was calculated from 6 points. The presence of early signs of atherosclerosis was defined as a local thickening of TCIM OCA over 0.86 mm at any point of the carotid arteries - TCIM OCA is maximum (Pignoli and Salonen, O'Leary et al., Cardiovascular Health Study: the CHS Collaborative Research Group. Stroke 23: 1752-1760, 1992). The criteria for the presence of ASB in the carotid arteries is a local thickening of the carotid artery by more than 50% in comparison with the surrounding areas or a thickening of the carotid artery by more than 1.5 mm with protrusion towards the lumen of the vessel.

For statistical analysis, we used the Fisher exact test, chi-square test, Student t-test, Biferroni test to assess the significance of differences between each pair of groups and the Tukey-Cramer multiple comparison criterion for recalculating multiple comparisons and multiple logistic regression for multivariate analysis (Hintze JL NCSS 2003 User Guide, Mann-Whitney Number Cruncher and Analysis of Variance Using Statistical Systems 2003 software NCSS, Kaysville, Utah).

The above method was applied to the examination of 111 outpatients with abdominal obesity with a waist circumference (RT) of ≥80 cm in women and ≥94 cm in men aged 18 to 59 years. Of these, 101 examined subjects confirmed various pathological changes in the liver tissue using the non-invasive Steatoscrin technique. The remaining 10 patients did not show signs of NAFLD and comprised a control group.

Also, all patients were divided according to the presence or absence of cytolysis syndrome and the degree of obesity.

Further, all the subjects underwent ultrasound examination of the carotid arteries.

In the first embodiment of the invention, when conducting a comparative statistical analysis, it was shown that the average TCIM OCA was significantly higher in patients with a combination of abdominal obesity and NAFLD than in the control group (Fig. 1).

Moreover, the maximum values of TCIM OCA were observed in patients with more severe pathological changes in the liver parenchyma (Fig. 2).

Atherosclerotic plaques were detected in 20% of patients (21 people) according to ultrasound examination of carotid arteries, while 94% of them showed pathological changes in the liver in the form of steatofibrosis - S4 level on the Steatoscrin scale (Fig. 3).

As a result of the correlation analysis, a reliably positive relationship was found between pathological changes in the liver tissue and the degree of thickening of CMM OCA (Fig. 4).

As a result of the regression analysis, a significantly positive dependence of the degree of thickening of CMM OCA on the severity of pathological changes in the liver diagnosed using a non-invasive bioprognostic test, Steatoscrin, was obtained. The obtained dependence is confirmed mathematically by a simple linear regression equation (Fig. 5).

Wed KIM y = 0.64 + 0.34 Steatoscrin

Clinical example:

Patient I., 48 years old. Steatoscrin results:

Height 164 The weight 105 Alpha2 Macroglobulin 3.18 haptoglobin 1,67 Alt 48,4 Ast 30,2 Glucose 5.48 Total x / s 6.95 Total bilirubin 10,2 Gamma GT 145.1 Apolipoprotein A1 1.29 Triglycerides 3.6

Patient I., 48 years old. Thickness parameters of CMM OCA according to the data of ultrasound examination of carotid arteries: KIM1 = 0.8; KIM2 = 0.76; KIM3 = 0.9; KIM cf. = 0.82 (mm).

We calculate TIM OSA cf. using the obtained regression equation:

CMM avg = 0.64 + 0.34 * 0.55 = 0.82 (mm). This value corresponds to the obtained results of ultrasound of the vessels of the neck.

In the second embodiment of the invention, when performing an ultrasound examination of the carotid arteries, the values of speed indicators of blood flow in the common carotid and internal carotid arteries were determined.

When conducting a comparative statistical analysis, it was shown that the average values of speed indicators of blood flow in the common carotid and internal carotid arteries were significantly higher in patients with a combination of abdominal obesity and NAFLD than in the control group (Fig. 6).

Moreover, the maximum speed parameters in the OCA and ICA were observed in patients with more severe pathological changes in the liver parenchyma (Fig. 7).

As a result of the correlation analysis, a significantly positive relationship was found between pathological changes in the liver tissue and an increase in blood flow in the CCA and ICA (Fig. 8).

Atherosclerotic plaques were revealed in 20% of patients (21 people) according to ultrasound examination of carotid arteries, while 94% of them showed pathological changes in the liver in the form of steatofibrosis - S4 level on the Steatoscreen scale, and the peak systolic velocity in the ICA exceeded the threshold value 110 cm / s (Fig. 9).

As a result of the regression analysis, a reliably positive relationship was obtained between the peak systolic blood flow velocity in the ICA and the severity levels of pathological changes in the liver, diagnosed using a non-invasive bioprognostic test - Steatoscrin. The obtained dependence is confirmed mathematically by simple linear regression equations (Fig. 10).

Clinical example:

Patient F., 41 years old. Steatoscrin results:

Height 179 The weight 106 Alpha2 Macroglobulin 3.68 haptoglobin 0.96 Alt 89 Ast 75 Glucose 5.74 Total x / s 3.64 Total bilirubin 9.23 Gamma GT fifty Apolipoprotein A1 1.3 Triglycerides 1.9

The values of speed indicators in the CCA and ICA according to the results of ultrasound of the vessels of the neck: 0.916 m / s and 1.41 m / s, respectively.

We calculate the numerical value on the Steatoscreen scale using the existing equation:

1. For OCA: Steatoscrin = 0.36604 + 0.44810 * 0.916 = 0.776, which corresponds to level 4 on the Steatoscrin scale.

2. For ICA: Steatoscreen = 0.40153 + 0.26419 * 1.41 = 0.777, which corresponds to level 4 on the Steatoscrin scale.

The results obtained by the clinical physician with the help of this invention are more easily explained and allow considering the possibility of a liver biopsy to clarify the etiology of the disease, either in the presence of severe liver fibrosis according to Steatoscrin, or if there is an obvious dissonance between the level of fibrosis established by the results of Steatoscrin , and clinical signs indicating a severe pathological process in the liver.

One of the significant discoveries of this work is an extremely significant improvement in the diagnostic value of liver pathology in the development of atherosclerotic lesions of the vascular wall.

Risk factors for the Steatoscrin system error were hemolysis, Hilbert's disease, acute inflammation, and extrahepatic cholestasis.

In conclusion, the present invention provides a combination of laboratory and instrumental methods: determination of 10 biochemical markers, adjusted for age, gender and BMI, for use in determining the presence or absence of steatosis or liver fibrosis and ultrasound examination of carotid arteries.

The diagnostic method according to the invention can be automated and can be advantageously used for patients with liver steatosis, including disease, to reduce the indications for liver biopsy.

Claims (6)

1. A method for determining atherosclerotic lesions of the vascular wall in patients with abdominal obesity and non-alcoholic fatty liver disease, including in vitro diagnosis of pathological changes in the liver Steatoscrin and determination of the value of Steatoscrin, characterized in that the average thickness of the intima-media of the carotid artery in a patient is determined by the formula Y = 0.64 + 0.34 Steatoscrin, and if Y≥0.86 mm, then the patient determines the early signs of atherosclerosis. 2. A method for determining atherosclerotic lesions of the vascular wall in patients with abdominal obesity and non-alcoholic fatty liver disease, including in vitro diagnosis of pathological changes in the liver Steatoscrin and determination of the value of Steatoscrin, characterized in that the peak systolic blood flow velocity in the internal carotid artery in a patient is determined by the formula Y = - 1.52 + 3.785 Steatoscrin, and if Y≥110 cm / s, then the patient determines the early signs of atherosclerosis.

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