CLINICAL COURSE FEATURES OF NON-ALCOHOLIC STEATOHEPATITIS ON OBESITY BACKGROUND IN COMORBIDITY WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

DOI: 10.24061/2413-0737. XXIV.1.93.2020.21

A number of these factors are also inherent in the pathogenesis of COPD, in particular, OS, NS, antioxidant deficiency, local and systemic inflammation, activation of fibroblasts with progression of bronchial remodeling and pneumosclerosis [1,2]. At the same time, β2 agonists, anticholinergics inhaled or systemic glucocorticoids, repeated courses of antibacterial drugs, which together can influence the development of dysmetabolic disorders and even hepatotoxic effects, are used in the treatment of COPD patients [2]. At the same time, the course of COPD stage 3-4 in patients of group D with a duration of more than 15 years is often complicated by the development of a chronic pulmonary heart disease, against which hepatomegaly, edematous-ascitic syndrome can be formed. Now the clinical features of the course of comorbidity of NASH and COPD are little studied, which necessitates the investigation of general developmental mechanisms, reciprocal mechanisms and the development of new methods for the correction of this comorbid pathology.

Aim of work:
To find out clinical, ultrasonographic and biochemical features of NASH course of obesity of the I grade, COPD of the 2-3 stages D comorbidities in comparison with the course of NASH with obesity without COPD by studying the frequency and intensity of leading clinical and biochemical syndromes, ultrasonographic (USG) characteristics of NASH depending on the presence of COPD.
Material and research methods. 105 NASH patients were examined: 52 among them of were NASH patients with grade I obesity (group 1) (men were 18, women were 24 people), 53 NASH patients with grade I obesity and COPD of the 2-3 stages D (28 males, 13 females) (group 2). To determine the dependence of NASH on COPD, groups of patients were randomized by age, degree of obesity. The average age of the patients was (55.7 ± 3.22) years.
The diagnosis of NASH was established according to the When patients were admitted to the hospital, the func-tional state of the liver was determined according to the generally accepted list of activity of enzymes, markers of pigment and nitrogen metabolism, proteinogram, lipidogram, ionogram, calculation of the De Ritis ratio. USG studies were performed to determine structural changes in the liver parenchyma. In order to quantify changes in liver echogenicity, the method of echodensitometry with the calculation of hepato-renal index (HRI) was used   [3,4,15]. Liver echodensitometry was performed on an empty stomach on an Ultima PA apparatus (Radmir, Kharkov, Ukraine) using a convex sensor (frequency 3-5 MHz) with subsequent digital histographic processing of USG images. HRI was calculated by the formula ): HRI = MNA/MNB [15]. All patients were performed anthropometry with determination of body mass index (BMI), waist circumference (WC), hip circumference (HC) and their ratio: waist/hip index (IWH=WC/HC). Statistical analysis of the results was carried out in accordance with the type of study and the types of numerical data that were obtained. The normality of the distribution was checked using the tests of Liliefors, Shapiro-Willkie and the method of direct visual assessment of histograms of the distribution of eigenvalues. Quantitative indicators that had a normal distribution, presented as mean (M) ± standard deviation (S). For nonparametric distribution, the data are presented as the median (Me) as a measure of position, upper (Q75) and lower quartile (Q25)  Pearson correlation analysis for parametric distribution and Spearman's rank correlation coefficient in the case of the distribution of indicators were used to estimate the degree of dependence between variables and that was significantly different from normal. To compare the discrete values in the independent groups, the log-likelhood criterion χ2 (MP χ2) was used, and the Fisher exact mid-p modification was used to compare the pairs of discrete quantities. Determination of the diagnostic superiority of the method was performed on the basis of the evaluation of the quality of diagnostic procedures using receiver operating characteristic (ROC analysis), with the calculation of indicators of sensitivity, specificity, diagnostic value, area under the ROC curve (AUROC), diagnostic odds ratio (DOR). Statistica for Windows software version 8.0 (Stat Soft inc., USA), Microsoft Excel 2007 (Microsoft, USA) we used for statistical and graphical analysis of the obtained results.
It should be noted that in the analysis of clinical manifestations of NASH in patients of the 2nd group the frequency and intensity were significantly higher. In particular, the symptoms of astheno-vegetative syndrome were observed 2.1 times more often (p <0.05) as compared to patients of the 1st group, which was probably associated with an increased accumulation of unmetabolized liver products in COPD exacerbation phase.
Manifestations of dyspepsia in patients in group 2 also occurred more often as compared to patients in group 1 (1.7 times (p<0.05)), indicating impaired digestive processes due to the allocation of defective bile composition, probably accompanying colorectal dysbiosis due to repeated courses of COPD antibacterial therapy, the attachment to central mechanisms of anorexia and nausea as a result of hypoxia.
Feeling of heaviness or pain on palpation in the right hypochondrium was recorded in patients of the 2nd group  Original research also with a frequency exceeding proper complain in patients of the 1st group by 2.5 times (p<0.05). There was no significant difference in the incidence of hepatomegaly in patients of groups 1 and 2 (p>0.05) (see Table 1). Clinically, cholestasis syndrome was found in 28.8% of NASH patients of the 1st group and in 62.3% of patients of the 2nd group, which was manifested by itching of the skin, bitter taste in the mouth, and the presence of xanthomatous formations on the eyelids. In a small number of patients of the 1st group, splenomegaly was established (13.5%), however, in patients of the 2nd group, the frequency of splenomegaly exceeded mentioned parameter in the 1st group, respectively, by 2.7 times (p<0.05). The syndrome of endocrine disorders was observed in all NASH patients in the form of grade I obesity. At the same time, IGT was found more often in the presence of COPD by 2.1 times (see Table  1). Among the biochemical syndromes in the examined patients of group 2, cytolytic (100.0%), cholestatic (73.6%) was found, which exceeded the frequency in the 1st group by 2.3 times (p<0.05), mesenchymal inflammatory which occurred with a higher frequency as compared to group 1 by 1.9 times (p<0.05), and HCF syndrome (50.9%), which occurred with a higher frequency as compared to group 1 by 2.6 times (p<0.05). So, the incidence of major clinical and biochemical steatohepatitis syndromes in NASH patients with concomitant COPD in comparison with the isolated course of NASH increased significantly (p<0.05).
When analyzing biochemical syndromes in NASH, most often the increase in average liver activity alanine aminotransferase (ALT) indicators in blood serum was found, which in NASH without COPD was by 3.1 times higher as compared to apparently healthy humans (AHH) (p<0.05) and aspartate aminotransferase (AST) by 2.4 times (p<0.05) ( Table 2). A significant decrease in the de Ritis factor (AST/ALT) was observed in 1.3 times (p<0.05), which, in the absence of positive markers of hepatitis B and C viruses in the serum, indicates non-alcoholic dysmetabolic and inflammatory liver disease. The confirmation of this fact were positive results of biochemical screening tests: SteatoTest and NASH-test (p<0.05) and negative results of ASH-test (p <0.05) in the examined patients, which excludes the alcoholic etiology of the disease.
In NASH patients with COPD, the cytolysis syndrome was more intense, since ALT activity exceeded in AHH by 3.8 times (p<0.05), and AST activity by 3.3 times (p<0.05), which led to a decrease in the de Ritis factor by 1.2 times (p<0.05) as compared to AHH (see table 2), since in addition to metabolic disorders in the pathogenesis of NASH and obesity in COPD conditions, it is likely to be involved the medication effects of drugs used in the treatment of exacerbation of COPD with hepatotoxicity [15].
The total bilirubin content in patients of group 2 exceeded the normative indexes by 1.9 times (p<0.05) as compared to 1.5 times in patients of group 1 (p<0.05). It should be noted that the level of total bilirubin in the blood of patients of group 2 increased due to an increase in both its fractions: conjugated -respectively by 2.3 times (p<0.05) versus 1.8 times (p<0.05) in 1 group, and unconjugated: excess by 1.8 times versus 1.3 times (p<0.05), respectively.
Mild manifestations of insufficiency of the protein-synthesis function of the liver in comorbidity with COPD were found in 50.9% of patients in group 2 and 19.2% of patients in group 1 by reducing the average total protein content (in 1.3 times (p<0.05) only in patients in group 2) and the content of albumin in the blood (in 1.4 times in patients in group 2 (p<0.05)), in the 1st group there was only a tendency to decrease these parameter (p>0.05). The presence of mesenchymal-inflammatory syndrome in NASH patients in the 2nd group was indicated by hyperglobulinemia (in 1.5 times (p <0.05)), an increase in the thymol test (in the 1st group -in 1.3 times (p < 0.05), in the 2nd group -in 1.6 times (p <0.05)), as well as the decrease of the albumin-globulin coefficient (A/G coefficient) (in the 1st group -in 1.3 times (p <0.05), group 2 -in 2.1 times (p <0.05) (see Table 2), which is also due to exacerbation of COPD.
USG of the liver of the examined patients revealed a high frequency and probable degree of hepatomegaly (Table 1), medium-grained transformation of the structure and mosaic induration (hyperechogenicity, "heterogeneity") of the liver parenchyma due to its inflammation, as well as a significant degree of hepatic steatosis (a significant percentage of dorsal attenuation of the USG signal).
The examined patients observed statistically significant increase in HRI (p<0.001). Thus, the median and 25th and 75th quartile values for HRI in AHH were 1.12 (1.0-1.26), in the 1st group 1.93 (1.75-2.18), in the 2nd group -2.46 (2.27-2.65). Analysis of OR by HRI in comparison groups (2 out of 1) indicates significant differences: OR=2.04 [CI 95% 1. 11-3.76]. An increase in HRI is associated with the amount of lipid accumulation in the liver parenchyma, as evidenced by the direct statistically significant strong correlation between the degree of steatosis (according to SteatoTest) and HRI (r = 0.81; p <0.001). However, in NASH patients, in the background of obesity changes in liver echogenicity due to the presence of non-alcoholic steatosis have been associated with anthropometric and laboratory parameters. A direct statistically significant various power association was established between HRI and HOMA-IR (r=0.71; p<0.001), BMI (r=0.64; p<0.001), WC/HC (r=0.57; p<0.001), ALT (r=0.38; p<0.05), ALP (r=0.33; p<0.05), γ-GT (r=0.28; p<0.05), the content of triacylglycerols in the blood (r=0.51; p<0.001). At the same time, in NASH patients with COPD, the correlation matrix has changed somewhat: a direct statistically significant higher strength of the relationship is established between HRI and HOMA-IR (r=0. 75 To determine the diagnostic significance of HRI we used ROC analysis, according to which the growth of this indicator is an effective marker of diagnosis of NASH, in which the AUROC for HRI was 0.97 (95% CI 1.06-2.98; p<0.001).
The threshold for HRI diagnosed with NASH was calculated to be > 1.48 and the sensitivity, specificity, PPV and NPV were 93.8%, respectively; 100%; 100% and 73.9%. Analysis of the results of the diagnostic test for patients with a comorbid course of NASH and COPD indicates that AU-ROC for HRI was 0.99 (95% CI 1.18-3.24; p<0.001), and sensitivity and NPV increased in accordance with 96.8% and 87.8% at the calculated optimal HRI threshold value > 1.52. A moderate threshold increase was observed for HRI in parallel with increasing diagnostic value.
3. The comorbid course of NASH with COPD is characterized by a higher degree of hepatic steatosis (HRI, OR=2.04 [CI 95% 1.11-3.76]) compared to the group of NASH patients without COPD (p<0.05). and a higher diagnostic threshold for hepatorenal index, which correlates strongly with the degree of hepatic steatosis determined by the Steato-test (r=0.81; p<0.001).
The prospect of further research in this area is the development of effective treatments for patients with comorbid course of NASH and COPD on obesity background.