KLINICZNE I PATOGENETYCZNE CECHY NIEALKOHOLOWEGO STŁUSZCZENIOWEGO ZAPALENIA WĄTROBY I WSPÓŁWYSTĘPUJĄCEJ ASTMY OSKRZELOWEJ NA PODŁOŻU OTYŁOŚCI

Oksana S. Khukhlina, Alona A. Antoniv, Olha Ye. Mandryk, Olha Yе. Hryniuk, Svitlana V. Kovalenko,
Victoria Yu. Drozd, Zoriana Ia. Kotsiubiichuk

Higher State Educational Institution of Ukraine “Bukovinian State Medical University”, Chernivtsi, Ukraine

ABSTRACT

Introduction: The comorbid flow of non-alcoholic steatohepatitis (NASH) and bronchial asthma (BA) on the background of obesity is often recently drawn to the attention of both practitioners and researchers .

The aim of our study was to study the changes in the functional state of the liver and the dependence of the external respiration function in patients with non-alcoholic steatohepatitis in combination with bronchial asthma and obesity.

Materials and methods: The study was attended by 50 people aged from 30 to 50 years (average age 42 years), of which 40% were men and 60% women. Of these, 30 patients with obesity I degree (BMI greater than 30 kg / m2) non-alcoholic steatohepatitis was detected, and in 20 of patients, non-alcoholic steatohepatitis was combined with obesity of the I degree and persistent bronchial asthma of moderate severity. Duration of the disease was from 2 to 6 years. The control group consisted of 20 practically healthy persons (PHPs) of the corresponding age and sex.

Results: In patients with NASH with comorbid BA and obesity I degree there are more noticed syndromes of cytolysis and cholestasis, mesenchymal inflammation, more significant changes in the liver, as evidenced by the low AST/ALT ratio in this group. Patients with non-alcoholic steatohepatitis on the background of obesity of the I degree with the addition of bronchial asthma of moderate severity and the persistent flow at the exacerbation phase, the content in the blood of markers of the activity of cytolysis of hepatocytes increases (increased activity of aminotransferases serum, p <0,05), cholestasis (increased content of direct bilirubin in the blood, p <0,05, cholesterol activity, p <0,05, gamma-glutamyltransferase activity, p <0,05 and alkaline phosphatase, p <0,05) and mesenchymal inflammation (increase in the thyme test, p <0,05), which testifies to the aggravating factor and the impact of BA on the course of NASH.

Conclusion: The presence of visceral obesity and nonalcoholic steatohepatitis in patients with bronchial asthma leads to the accumulation of its clinical course, the deepening of changes in the function of external respiration by obstructive type (a possible decrease in FEV1 and PEF, p<0.05). The presence of obesity and NASH contributed to the development of restrictive type of respiratory insufficiency in the form of a possible decrease in Vital capacity (VC, p<0,05) in patients without BA, and in patients with NASH and obesity with BA, which significantly aggravated its course.

 

Wiad Lek 2018, 71, 2 cz. I, -379

 

Introduction

The prevalence of non-alcoholic steatohepatitis (NASH) is globalized among the population of economically developed countries with a growing trend in Ukraine. The frequency of NASH, according to various authors, ranges from 20% to 35%, which directly affects the quality of life of patients, promotes the progression of disorders of all types of exchange and development of liver and cellular insufficiency [1, 2, 3]. The increasing prevalence of bronchial asthma (BA) and the need for its long-term basic treatment [4], deterioration of the environment, frequent use of xenobiotics in home, etc., cause the combination of BA with the digestive system diseases [5,6], in particular nonalcoholic steatohepatitis [7, 8]. It is detected in populations of different countries in 10-24% of cases, regardless of age and race characteristics [9,10,11,12]. The combination of BA and NASH contributes to the increase in the severity of the underlying disease and the earlier formation of complications.

The aim

The purpose of our study was to study the changes in the functional state of the liver and the dependence of the external respiration function in patients with non-alcoholic steatohepatitis in combination with bronchial asthma and obesity.

Materials and methods

The study was attended by 50 people aged from 30 to 50 years (average age 42 years), of which 40% were men and 60% women. Of these, 30 patients with obesity I degree (BMI greater than 30 kg / m2) non-alcoholic steatohepatitis was detected, and in 20 of patients, non-alcoholic steatohepatitis was combined with obesity of the I degree and persistent bronchial asthma of moderate severity. Duration of the disease was from 2 to 6 years. The control group consisted of 20 practically healthy persons (PHPs) of the corresponding age and sex.

To evaluate the functional state of the liver, biochemical tests were performed: total bilirubin, conjugated and unconjugated bilirubin content, thymol test, proteinogram, coagulogram, lipid profile, blood amylase activity, electrolytes, enzyme activity: alanine aminotransferase (ALT), aspartate aminotransferase (AST ), alkaline phosphatase (ALKP), gamma-glutamyltransferase (γ-GT), urea content and creatinine in blood, which were determined using unified methods approved by the Ministry of Health of Ukraine. Ultrasonography of the abdominal cavity is performed on 100% of patients. Functional liver tests were evaluated in combination with clinical data.

The study of the function of external respiration in patients was performed using spirometry with the analysis of the flow-volume curve, forced exhalation (determination of FEV1, LVC, FVC); samples with bronchodilators (at the value of FEV1 60% – 80% of proper) to establish the reversibility of bronchoconstriction; determination of the gas composition of blood (with FEV1> 30% of due or if the lack of respiration corresponds to FEF). Parameters of the expiratory breathing function (FEF) were determined using the computer spirograph “BTL-08 SpiroPro” (Great Britain).

The following indices were defined, which characterize the ventilation capacity of the lungs and bronchial patency: LVC – lung capacity, FEV1 – the volume of forced exhalation in the first second, FLVC – forced LVC, the ratio FEV1 / FVLC, PEF – peak expiratory rate.

The statistical analysis of the results was carried out in accordance with the type of research carried out and the types of numerical data that were obtained. Distribution normality was verified using Liliefors, Shapiro-Uilka tests and the direct visual evaluation of eigenvalues distribution histograms. Quantitative indices having a normal distribution are represented as mean (M) ± standard deviation (S). In a nonparametric distribution, the data is presented as median (Me) as position, upper (Q75) and lower quartile (Q25) as a measure of scattering. Discrete values are presented in the form of absolute and relative frequencies (the percentage of observations to the total number of subjects surveyed). For comparisons of data that had a normal distribution pattern, parametric tests were used to estimate the Student’s t-criterion, Fisher’s F-criterion. In the case of abnormal distribution, the median test, Mann-Whitney Rank U-Score, and Wilcox’s T-criterion (in the case of dependent groups) were used for multiple comparison. Statistica for Windows version 8.0 (Stat Soft inc., USA), Microsoft Excel 2007 (Microsoft, USA) software packages were used for statistical and graphical analysis of the obtained results.

Results and discussion

Biochemical blood test in patients with NASH combined with BA and obesity revealed changes in the parameters characterizing the functional activity of the liver (Table I).

Taking into account the data presented in the table, patients of Group 1 showed a decrease in the de Ritis factor (AST / ALT ratio) by 24.3% (p<0.05), which, in the absence of positive markers of hepatitis B and C viruses in serum, indicates non-alcoholic dysmetabolic and inflammatory liver disease.

The activity of the alanine aminotransferase (ALT) (Table I) exceeded the index in PHP by 3.0 times (p <0.05), while the activity of aspartate aminotransferase (AST) (Table I) was exceeded 2.1 times (p <0.05 ), which led to a decrease in the de Ritis factor by 28.2% (p <0.05) compared with PHP, indicating a more intense cytolysis syndrome in group 2. The probable increase in the total bilirubin content in patients of the group 2 was 2.2 times (p <0.05) compared with 1.5 times in patients of group 1 (p <0.05) compared with the group of PHPs. It should be noted that both fractions of the total bilirubin increased: the conjugated – 2.9 times (p <0,05) and 1.9 times (p <0,05) in the 1st group, respectively, and unconjugated: excess in 2,0 and 1,3 times respectively (p <0,05).

The presence of mesenchymal-inflammatory syndrome in NASH in conjunction with BA indicated an increase in the thyme sample, which was also the maximum in the 2nd comparison group (p <0.05) (Table I).The increase in activity of alkaline phosphatase (ALKP) by 35.0% (p <0.05) in patients with NASH and BA with obesity I degree (group 2) and 20.8% (p <0.05) in patients of group 2, gamma-glutamyltransferase (γ-GT) activity was 30.4% versus 19.2% (p <0.05) and bile acid content in blood, which exceeded the indexes in PHP by 2.3 and 1.9 times respectively (p <0,05) indicates the presence of cholestasis, which was also maximum expressed in patients in the 2nd group.Thus, in patients with NASH with comorbid BA and obesity I degree, there are more noticed syndromes of cytolysis and cholestasis, mesenchymal inflammation, and more significant changes in the liver, as evidenced by the low index de Ritis factor in this group.

Results of the study of the function of external respiration (FEF) in patients with NASH in comorbidity with BA and obesity I degree showed statistically significant differences in the parameters of the forced vital capacity of the lungs (FLVC) and the volume of forced exhalation for the first second (FEV1), peak volume exhalation velocity (PEF). In patients of the 2nd group, FEV1 was significantly lower, indicating the presence of BA (Table II).

However, in patients with NASH and obesity without BA, the average FEV1 values were (82,45 ± 2,31)%, which is significantly different from that in PHPs (compared to PHPs (88,78 ± 1,97)%). In patients with comorbid BA, the indicator was (61.13 ± 1.23)% (p <0.05) of the proper values, which reflects the average severity of the persistent flow of BA with an appropriate degree of bronchial obstruction. In the 2nd group PEF equaled (44,32 ± 1,65)%, and in patients with NASH and obesity without BA (72,11 ± 1,06)% (p <0,05), which also indicates a decrease of this indicator in the 1st group and the contribution of NASH and obesity in the formation of broncho-obstructive syndrome (BOS). Characteristic spirographic signs of a violation of bronchial patency in patients with BA are a decrease in the Tiffeneau-Pinelli index (TI, the ratio FEV1 / FLVC), as a rule, less than 70%. In patients with a combined course of BA, NASH and obesity, there is a probable decrease in the index compared with other groups (p <0,05) due to the presence of BA. At the same time, we have established a decrease in TI in patients of group 1 by 7.2% (p <0.05), which confirms the role of obesity and NASH in the formation of BOS.

The LVC in patients with NASH, obesity and BA was significantly lower in comparison with PHPs (57.34 ± 1.09)%, while it was not significantly different from that in group 1 patients (62.87 ± 2.22%) ( p> 0.05). That is, changes in volumetric FLVC rates indicate the presence of restrictive changes in patients with BA on the background of obesity, and in patients with obesity with NASH, which is due to obesity. Increased intraabdominal pressure due to excessive accumulation of fat in the abdominal cavity contributes to the high position of the diaphragm dome and to the reduction of pneumatisation of the lower lung, limitation of the respiratory area of the lungs, which significantly reduces the intensity of gas exchange, both in and without the accompanying BA.

The correlation analysis between LVC and BMI in patients showed a reverse average correlation between these parameters: the correlation coefficient r = -0.37 (p <0.001). Correlation between FEV1 and BMI in the examined patients was weak (r = -0.29; p <0.05).

The prospect of further research in this direction is the study of oxidant-antioxidant status under the influence of various hepatotropic drugs under the comorbidity of NASH with BA.

Conclusions

1. In patients with non-alcoholic steatohepatitis on the background of obesity of I degree with bronchial asthma of average severity and persistent flow in phase of exacerbation, the content of the hepatocyte cytolysis activity markers in the blood (increased activity of aminotransferases serum, p <0,05), cholestasis (increase in content of conjugated bilirubin, p <0.05, cholesterol, p <0.05, gamma-glutamyltransferase activity, p <0.05 and alkaline phosphatase, p <0.05) and mesenchymal inflammation (increase in thyme sample, p <0.05) ) increases, which indicates the strong effect of bronchial asthma on the course of NASH.

2. The presence of visceral obesity and non-alcoholic steatohepatitis in patients with bronchial asthma leads to the aggravation of its clinical course, the deepening of changes in the function of external respiration by obstructive type (a possible decrease in FEV1 and PEF, p <0.05). The presence of obesity and NASH contributed to the development of restrictive type of respiratory insufficiency in the form of a possible decrease in LVC (p <0,05) in patients without asthma, and in patients with NASH and obesity with BA, which significantly aggravated its course.

References

1. Carmen N.B. Oxidative stress in the formation of hypoxia in severe bronchial asthma.Pulmonology.2011;12: 65-678.

2. Dolzhenko M.M., Bazilevich Av.Ya., Nosenko N.M. The influence of non-alcoholic fatty liver disease on the course of ischemic heart disease according to two-year observations. Ukr. cardiology magazine. 2011;2:67-70.

3. Chitturi S., Farrell G.C. Etiopathogenesis of nonalcoholic steatohepatitis. Semin. Liver Dis. 2001;21(1):27–41.

4. Bueverov AO, Bogomolov PO. Non-alcoholic fatty liver disease: rationale for pathogenetic therapy. Clinical perspectives in gastroenterology, hepatology. 2009;1:3-9.

5. Almeda–Valdés P, Cuevas–Ramos D, Aguilar–Salinas CA. Metabolic syndrome and non–alcoholic fatty liver disease.Ann. Hepatol. 2009; 8(1):18–S24.

6. Bambha K, Belt P, Abraham M, et al. Ethnicity and nonalcoholic fatty liver disease. Hepatology.2012;55(3):769–780. [PubMed]

7. Bereznicki BJ, Peterson GM, Jackson SL, Walters EH, Fitzmaurice KD, Gee PR. Datamining of medication records to improve asthma management. Med J Aust. 2008 Jul 7;189(1):215.

8. Aly FZ, Kleiner DE. Update on fatty liver disease and steatohepatitis. Adv. Anat. Pathol. 2011; Vol.18,4: 294–300.

9. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J. Clin. Gastroenterol.2006; Vol.40,1:5–S10.

10. Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2012; 35:66–75.

11. Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA; NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53:810–20. doi: 10.1002/hep.24127. Epub 2011 Feb 11. PMID: 21319198

12. Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10(11):666–675. [PubMed]

 

 

This work is a fragment of the research work “Pathogenetic mechanisms of mutual burden and clinical features of non-alcoholic fatty liver disease and chronic kidney disease, justification of differentiated treatment”, registration number 0117U002351 (2017-2019).

ADDRESS FOR KORRESPONDENCE

Alona A. Antoniv

Department of Internal Medicine,

Clinical Pharmacology and Occupational Diseases,

Higher Educational Establishment of Ukraine

“Bukovinian State Medical University”, Chernivtsi, Ukraine,

tel.: +380992321861

e-mail: antonivalona@ukr.net

Received: 20.02.2018

Accepted: 10.04.2018

Table I. Indicators of the functional state of the liver in patients with non-alcoholic steatohepatitis depending on the presence of comorbid bronchial asthma and obesity in comparison with a group of practically healthy persons.

Indicators, Units

PHPs, n=20

Groups of surveyed patients

   

NASH+ Obesity

(Group 1), n=30

NASH+ Obesity+BA

(Group 2), n=20

Total bilirubin, μmol/l

19,20±1,15

28,2±1,25 *

42,5±1,17 */**

Direct bilirubin, μmol/l

4,51± 0,27

8,6±0,23 *

13,2±0,42 */**

Indirect bilirubin μmol/l

14,70±0,43

19,6±1,21 *

29,3±1,15 */**

AST, μmol/hour×l

0,49± 0,013

0,88±0,023 *

1,05±0,025 */**

ALT, μmol/hour×l

0,48± 0,017

1,13±0,012 *

1,42±0,013 */**

de Ritis factor

1,02± 0,021

0,78±0,007 *

0,74±0,006 */**

Gamma-GT, mmol/hour×l

5,21± 0,135

6,23±0,125*

6,78±0,131*/**

ALKP, mmol/hour×l

1,20± 0,011

1,45±0,013 *

1,62±0,021 */**

Bile acid, mmol/l

1,21± 0,021

2,37±0,025 *

2,79±0,058 */**

Thymol test, c.u.

2,79± 0,134

3,34±0,121 *

3,95±0,137 */**

* – the difference is probable compared to the indicator for practically healthy persons (p <0,05);

** – the difference is probable compared with the index in patients with NASH (1 gram) (p <0,05).

Table II. Changes in the parameters of external respiration in patients with bronchial asthma depending on comorbid NASH and obesity

Indicator, %

Groups of surveyed patients

 

PHP, n=20

NASH+ Obesity

(Group 1), n=30

NASH+ Obesity+BA

(Group 2), n=20

LVC, %

82,78±1,97

62,87±2,22*

57,34±1,09*

FEV1, %

88,78±1,97

82,45±2,31*

61,13±1,23*/**

FLVC, %

93,31 ± 2,56

81,18±1,02*

52,43±2,01*/**

FEV /FLVC, %

86,92 ± 1,34

80,63±0,42*

42,41±2,70*/**

PEF, %

79,12±2,41

72,11± 1,06*

44,32±1,65*/**

* – the differences are probable (p <0,05) in comparison with the PHP;

** – the difference is probable compared to the rate for patients with NASH and Obesity 1 degree (p <0.05).