Criteria of Formation of Fatty Liver Disease in Individuals of Different Age Groups in the Long-Term Period after Minimally Invasive Cholecystectomy

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LIST OF ABBREVIATIONS

AD — arterial pressure

BMI — body mass index

CE — cholecystectomy

CL — cholelithiasis

DAP — diastolic arterial pressure

DOS — dysfunction of Oddi sphincter

FLD — fatty liver disease

МРI — magnetic resonance imaging

MRCPG — magnetic resonance cholangiopancreatography

PCCES — postcholecystectomy syndrome

PDFF — proton density fat fraction

PR — pulse rate

SAP — systolic arterial pressure

US — ultrasound

WHO — World Health Organization

INTRODUCTION

The incidence of cholelithiasis (CL) is currently taking catastrophic proportion — today the disease affects about 20% of the adult population. With this, women are affected 5 times more often than men, due to frustration of estrogenic background in the pathogenesis of gallstone formation [1]. In Russia alone, more than 100,000 cholecystectomies are performed annually. In the current stage of development of surgical treatment of CL, minimally invasive laparoscopic methods are widely used permitting to considerably reduce traumatic character of the surgery and shorten the rehabilitation period [2].

Even the use of the latest technologies does not always permit to obtain complete healing in the long-term period. More than 40% of operated patients complain of different disorders of the regulation of the gastrointestinal tract, often accompanied by pain and discomfort, which significantly reduces the quality of life of such patients [3]. The sympathocomplex of disorders of the digestive system directly related to surgical intervention was given the collective name ‘postcholecystectomy syndrome’ (PCCES) [4].

The consequences of cholecystectomy are not always associated with the biliary tract. In approximately 40% of cases of long-term postoperative disorders, fatty liver disease (FLD) develops due to both general etiological factors and pathogenetic peculiarities of passage of bile after the loss of the gall bladder [5–7].

The pathogenesis of FLD includes formation of insulin resistance and impaired excretion of cholesterol leading to increase in the infiltration of hepatocytes with lipids [8–10]. One of the key elements of pathogenesis is dysfunction of Oddi sphincter (DOS) which deranges the passage and recirculation of bile with the result of reduction of its bactericidal properties and excessive bacterial growth in the intestine [11, 12]. An important contribution to the formation of FLD after CE is made by the autonomic nervous system, therefore, in predicting postoperative outcomes, it is necessary to take into account the peculiarities of autonomic regulation and the age of patients.

The aim of this study to find prognostic criteria for the formation of fatty liver disease in the remote period after cholecystectomy and to scientifically substantiate their significance.

MATERIALS AND METHODS

To develop prognostic criteria for the formation of FLD in the long-term period after laparoscopic minimally invasive CE, clinical data of 330 patients (159 men and 171 women) who underwent planned surgical treatment, were analyzed.

Exclusion criteria: a coarse pathology of digestive, respiratory and circulatory system, hepatic steatosis, hepatic cirrhosis, active hepatitis, diabetes mellitus, alcoholism and oncologic diseases in the preoperative period.

On admission to hospital, patients signed a standard for a medical institution form of Informed content. The results of standard clinical procedures for this category of patients were analyzed on our clinical base, no other clinical intervention were conducted, so no approval of the Ethic Committee was required.

Patients included into the study, were divided to three age subgroups: subgroup 1 — from 45 to 59 years; sub-group 2 — from 60 to 74; subgroup 3 — above 75 (Table 1).

 

Table 1. Demographic Parameters of Analyzed Sample of Patients Who Underwent Cholecystectomy

Gender	Age Subgroups
	First	Second	Third
	45–59 years	60–74 years	above 75 years
Men	50	68	41
Women	67	70	39

 

A year after the operation, according to the results of the instrumental examination which included elastography and magnetic resonance imaging (MRI), the studied patients were divided to two groups — a group of patients with signs of fatty hepatosis and patients with no fatty alterations of the liver.

Patients were divided to groups depending on the severity of the echographic signs of the formation of the FLD according to the method of S. S. Batskov, that included assessment of liver enlargement, visualization of hepatic veins, measurement of distal attenuation of sound, verification of parenchymal hyperechogenicity, fixation of the diaphragmatic contour, determination of angioarchitectonics of hepatic veins, determination of the degree of expansion of the portal vein diameter and splenomegaly (Table 2).

 

Table 2. Degree of Fatty Liver Disease by S. S. Batskov Method a Year after Cholecystectomy in Age Groups of Men and Women, n

Degree	First Group	Second Group	Third Group
	45–59 years	60–74 years	above 75 years
Men
I degree	21	22	15
II degree	5	8	4
III degree	–	2	–
IV degree	–	–	–
Women
I degree	27	25	18
II degree	4	9	2
III degree	–	–	1
IV degree	–	–	–

 

The results were more precisely defined using the quantitative evaluation of fatty hepatosis through measurement of fat concentration determined by proton density fat fraction (PDFF). PDFF was calculated by dividing the quantity of fat protons in the liver by the total quantity of protons in the liver (Table 3). To evaluate the degree of FLD by MRI-determined proton density, the scoring system of D. E. Kleiner, et al. was used [13–15] (Table 4).

 

Table 3. Criteria Used in Evaluation of Fatty Liver Disease Degree [13–15]

Degree	Condition	% of Fat Concentration
0	No fatty hepatosis	≤ 5
1	Mild fatty hepatosis	from 5 to 33
2	Moderate fatty hepatosis	from 33 to 66
3	Severe fatty hepatosis	> 66

 

Table 4. Results of Instrumental Examination in a Year after Cholecystectomy, M ± σ

Parameters	Control			Fatty Liver Disease
	First Group	Second Group	Third Group	First Group	Second Group	Third Group
	45–59 years	60–74 years	above 75 years	45–59 years	60–74 years	above 75 years
Men
Elastography, kPa	5,8 ± 1,3	6,2 ± 0,9	6,1 ± 1,1	8,7 ± 1,4*	9,3 ± 0,7*	9,6 ± 0,5*
Liver MRI, % of fat	2,2 ± 1,8	4,1 ± 1,5	3,6 ± 2,1	17,6 ± 3,8	21,3 ± 7,3	25,4 ± 6,2
Women
Elastography, kPa	5,4 ± 0,9	6,1 ± 1,2	6,3 ± 0,7	8,3 ± 1,5*	9,7 ± 0,8*	9,5 ± 1,1*
Liver MRI, % of fat	2,5 ± 1,6	3,2 ± 1,3	3,1 ± 1,8	12,5 ± 5,2*	24,6 ± 8,2*	26,3 ± 7,2*

Note: MRI — magnetic resonance imaging; * — to the control group, p < 0.001

 

By all parameters of the instrumental methods, statistically significant differences of the degree of liver infiltration with fat were determined that permitted to diagnose FLD and divide the groups by its presence (Table 5). FLD of different degree was determined after CE in 77 of 159 of study men and in 86 of 171 women.

 

Table 5. Distribution of Analyzed Sample of Patients Depending on Existence of Fatty Liver Disease in a Year after Cholecystectomy, n

Gender	Control, n = 167			Fatty Liver Disease, n = 163
	First Group	Second Group	Third Group	First Group	Second Group	Third Group
	45–59 years	60–74 years	above 75 years	45–59 years	60–74 years	above 75 years
Men	24	36	22	26	32	19
Women	31	36	18	31	34	21

 

After that, anthropometric data were evaluated, body mass index (BMI) was calculated in kg/m2. Hemodynamic parameters were determined:

- pulse rate (PR) by palpation in the projection of the radial artery;

- arterial pressure (AP including systolic (SAP) and diastolic (DAP)) was measured by Korotkoff method;

- autonomic index (Kérdö index) was calculated by the formula:

Kérdö index = (1 — DAP / Pulse) × 100,

where IKérdö — autonomic index, DAP — diastolic pressure.

Vagotonia — predomination of parasympathetic tone was determined by Kérdö index > (-1.6); amphotonia — the balance between sympathetic and parasympathetic tone was determined by the index value from (-1.5) to +1.5; sympathicotonia — by the index value > (+1.6).

For ultrasound evaluation of choledoch and liver elastography, Vivid S60 scanner (General Electric, USA), with curvilinear transducer 3–5 МНz was used. Examination to evaluate DOS was performed in the morning, the second examination was performed after cholecystectomy (during the second examination, no choleretic drugs were used) (7).

The data on the choledoch diameter obtained by ultrasound examination (US) were made more exact in magnetic resonance cholangiopancreatography (MRCPG). Determination of FLD degree and MRCPG [16, 17] were performed using Magnetom Aera 1.5T tomograph (Shimadzu, Japan). The quantitative and qualitative composition of the parietal intestinal microbiota was determined on Shimadzu LCMS 8030 triple quadrupole mass spectrometer (Shimadzu, Japan).

Statistical analysis of the results was performed in the Office 2010 (Microsoft, USA), Statistica application software package for Windows 10.0 (Microsoft, USA). The character of the distribution of variables was determined using Kolmogorov– Smirnov test. The obtained results indicated normal distribution, which was the reason for using parametric statistical methods for subsequent data analysis. The results are presented in the form of M — arithmetic mean and σ — standard deviation. For comparison between the groups, Student's t-test for independent samples was used. The differences were considered statistically significant at p < 0.05.

RESULTS

No differences in the anthropometric parameters between the group of FLD and the control group were found (Table 6).

 

Table 6. Anthropometric Data in Analyzed Sample of Patients, M ± σ

Parameters	Control			Fatty Liver Disease
	First Group	Second Group	Third Group	First Group	Second Group	Third Group
	45–59 years	60–74 years	above 75 years	45–59 years	60–74 years	above 75 years
Men
Age, years	53.2 ± 3.8	66.8 ± 3.7	76.7 ± 1.5	52.4 ± 4.6	66.7 ± 4.5	77.2 ± 1.5
Weight, kg	85.4 ± 11.2	95.7 ± 7.3	72.4 ± 6.4	92.8 ± 16.8	103.4 ± 11.1*	81.0 ± 11.6*
Height, cm	177.6 ± 5.8	176.6 ± 6.5	174.5 ± 4.9	177.7 ± 7.1	178.4 ± 6.7	175.5 ± 6.7
Body mass index, kg/m2	27.4 ± 2.5	28.9 ± 1.6	23.4 ± 1.5	29.3 ± 4.6	33.1 ± 1.2*	27.3 ± 1.9*
Women
Age, years	50.2 ± 3.7	66.5 ± 3.7	80.1 ± 2.6	50.0 ± 3.9	65.6 ± 4.0	79.0 ± 2.5
Weight, kg	78.6 ± 11.5	84.7 ± 10.3	64.2 ± 12.6	85.6 ± 13.2	90.9 ± 11.1*	69.8 ± 15.4*
Height, cm	167.2 ± 8.5	165.8 ± 8.1	161.5 ± 7.3	166.3 ± 9.3	166.1 ± 7.6	161.1 ± 8.2
Body mass index, kg/m2	28.9 ± 1.7	29.3 ± 1.3	24.2 ± 1.2	30.2 ± 2.3	32.8 ± 1.8*	26.8 ± 1.3*

Note: * — to the control group, p < 0.001

 

With that, higher parameters of BMI and weight were recorded in patients with FLD (both men and women) in the second and third age subgroups compared with the control group of the same age. Thus, the relationship between the formation of fatty liver disease and increased body weight was determined in patients of older age operated on for cholelithiasis.

The pulse rate in both men and women in most cases increased with age, and in the first age group in patients with developing FLD more significantly than in the control group (Table 7). A year after CE, no significant changes in pulse rate were detected. SAP at an older age, with rare exceptions, was higher than in the first age group and practically did not change within a year after CE. DAP changed without any visible pattern. In men, a year after CE, higher levels of DAP were observed in the first and third subgroups relative to the control group, and in the second age subgroup, on the contrary, lower than in the first group. In the second age subgroup of women, who subsequently developed FLD, DAP levels before surgery were lower. A year after CE, oppositely directed changes were noted relative to the control group: in the second subgroup they decreased, and in the third they increased.

 

Table 7. Parameters of Hemodynamics and Autonomic Status in Patients of Different Age Who Underwent Cholecystectomy, Depending on Formation of Fatty Liver Disease, M ± σ

Parameters

Before Cholecystectomy

In a Year after Cholecystectomy

Control

Fatty Liver Disease

Control

Fatty Liver Disease

First Group

Second Group

Third Group

First Group

Second Group

Third Group

First Group

Second Group

Third Group

First Group

Second Group

Third Group

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

Men

Pulse rate

72.1 ± 3.5

76.3 ± 3.6#

78.5 ± 2.7#

77.1 ± 2.2*

77.6 ± 5.2

79.6 ± 2.4#

73.2 ± 2.8

77.1 ± 3.2#

76.5 ± 1.3#

78.3 ± 3.7*

76.5 ± 4.1

78.3 ± 4.6*

Systolic arterial pressure

127.3 ± 2.4

135.2 ± 5.4#

141.4 ± 5.1#

127.1 ± 4.7

141.7 ± 11.3#*

147.4 ± 7.2#*

124.7 ± 2.7

135.6 ± 7.3#

139.2 ± 5.7#

142.6 ± 8.1&*

137.5 ± 7.9&

139.4 ± 8.1&

Diastolic arterial pressure

75.7 ± 4.3

77.4 ± 3.3

76.5 ± 2.2

74.3 ± 3.1

75.2 ± 4.8

78.2 ± 3.7#

73.3 ± 3.2

75.8 ± 2.8

73.4 ± 3.5

82.1 ± 3.1*&

74.4 ± 3.6#

77.2 ± 7.2#*

Autonomic index

-4.9 ± 1.2

-1.4 ± 0.5#

2.6 ± 1.3#

3.8 ± 0.7*

3.1 ± 0.7*

1.4 ± 0.7*#

-1.6 ± 0.5&

1.7 ± 1.4#

3.9 ± 1.5#&

4.8 ± 1.3*&

2.8 ± 0.7*#

1.5 ± 0.4*#

Women

Pulse rate

74.3 ± 3.2

75.4 ± 4.1

77.6 ± 3.1#

77.2 ± 3.2*

76.3 ± 2.3

77.4 ± 5.2

71.2 ± 2.4&

75.4 ± 3.2#

74.5 ± 2.9#

78.4 ± 4.2*

74.3 ± 3.9

76.4 ± 5.1

Systolic arterial pressure

125.2 ± 3.5

129.1 ± 2.6#

131.3 ± 5.4#

127.3 ± 4.2

141.5 ± 8.6*#

147.5 ± 6.4*#

122.3 ± 3.5

125.5 ± 8.7

129.6 ± 8.5*#

140.3 ± 7.5&

139.7 ± 12.1*

137.5 ± 7.8&*

Diastolic arterial pressure

76.7 ± 3.6

77.3 ± 3.1

76.7 ± 4.1

74.5 ± 3.7

73.6 ± 5.1*

76.1 ± 2.7

74.5 ± 2.1

77.2 ± 4.1

71.3 ± 2.8#&

75.3 ± 2.9

72.5 ± 3.8*

77.6 ± 5.7*

Autonomic index

-3.2 ± 1.7

-2.5 ± 1.2#

1.2 ± 1.4#

3.5 ± 1.4*

2.4 ± 1.9*#

1.7 ± 1.4#

-4.6 ± 3.1&

-2.4 ± 1.5#

4.3 ± 1.7#

4.0 ± 1.5*

2.4 ± 1.2*#

-1.6 ± 0.8*#

Notes: * — to the control group, p < 0.001; # — to the analogous first age group, p < 0,001; & — to the period preceding cholecystectomy, p < 0.001

 

In evaluation of the autonomic status, of attention was the fact that in patients of the first age category of both genders with developed FLD, sympathetic tone predominated before and after CE, and in the control group of the same age, vagotonia predominated (Tables 7, 8). At an older age, in the second and third subgroups of patients with FLD, both amphotonia and poorly expressed sympathicotonia were determined.

 

Table 8. Number of Patients with Fatty Liver Disease Depending on Age, Gender and Autonomic Status, n (%)

Vegetative status	Control			Fatty Liver Disease
	First Group	Second Group	Third Group	First Group	Second Group	Third Group
	45–59 years	60–74 years	above 75 years	45–59 years	60–74 years	above 75 years
Men
Patients with Sympathicotonia	5 (21)	8 (23)	11 (50)	19 (72)	20 (61)	4 (21)
Patients with vagotonia	15 (63)	5 (12)	3 (15)	3 (12)	8 (26)	5 (26)
Patients with amphotonia	3 (16)	23 (65)	8 (35)	4 (16)	4 (13)	10 (53)
Women
Patients with Sympathicotonia	5 (15)	6 (16)	10 (54)	19 (62)	16 (47)	6 (28)
Patients with vagotonia	18 (58)	17 (48)	4 (23)	5 (15)	7 (21)	4 (19)
Patients with amphotonia	8 (27)	13 (36)	4 (23)	7 (23)	11 (32)	11 (53)

 

Distribution of patients depending on the autonomic status showed that among men with FLD formed in a year, there were 72% with sympathicotonia in the first group, 61% in the second and only 21% in the third group. Among women with FLD, there were 62% with sympathicotonia in the first group, 47% in the second, and 28% in the third. With this, in the groups of men and women without FLD, in patients of younger age and in the first age subgroup, vagotonia prevailed. Thus, there is a relationship between formation of FLD and the autonomic status; until 60, the formation of FLD after CE is associated with predomination of sympathetic tone, with age this relationship decreases and after 75 the autonomic status does not influence the formation of this disease.

Dysfunction of Oddi sphincter that was evaluated by increase in the width of the choledoch, signs of dysfunction were to a higher extent present in patients with FLD developed in a year after the surgery. The results of the width of choledoch obtained by US and MRCPG completely coincided by the degree of expansion and direction. In the groups of both men and women with FLD ,the parameters of width of choledoch were greater relative to the control group. Besides, parameters in these groups also changed relative to the preoperative period. In patients with FLD under 60, the choledoch diameter was greater than in older patients of the same group. In older groups without FLD, increase in the width of choledoch was determined relative to the first age subgroup and to the preoperative period (Table 9).

 

Table 9. Diameter (M ± σ, mm) of Choledoch after Cholecystectomy Depending on Formation of Fatty Liver Disease

Study method

Before Cholecystectomy

In a Year after Cholecystectomy

Control

Fatty Liver Disease

Control

Fatty Liver Disease

First Group

Second Group

Third Group

First Group

Second Group

Third Group

First Group

Second Group

Third Group

First Group

Second Group

Third Group

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

Men

Ultrasound examination

5.2 ± 0.7

4.6 ± 0.5#

4.8 ± 0.6

5.5 ± 1.1

4.9 ± 1.2

5.3 ± 0.8

4.8 ± 0.6

5.6 ± 1.5#&

5.4 ± 1.3#&

9.4 ± 1.7*&

8.1 ± 1.1*#&

7.3 ± 1.4*#&

Magnetic resonance cholangiopan-creatography

7.2 ± 0.7

6.7 ± 0.5#

7.1 ± 1.4

7.6 ± 0.6

7.1 ± 0.8

7.3 ± 0.9

6.7 ± 0.7

7.2 ± 1.2#&

7.3 ± 0.9&

12.1 ± 1.4*&

10.2 ± 1.2*#&

9.3 ± 1.2*#&

Women

Ultrasound examination

5.3 ± 0.6

4.5 ± 0.7#

4.7 ± 0.3

5.7 ± 0.9

5.1 ± 1.1

5.7 ± 1.2

4.9 ± 0.7

4.8 ± 1.2#

5.4 ± 1.3#&

8.5 ± 1.3*&

7.6 ± 1.6*#&

7.3 ± 1.2*#&

Magnetic resonance cholangiopan-creatography

7.5 ± 0.3

7.1 ± 0.4#

7.2 ± 1.1

7.8 ± 1.2

7.3 ± 0.7

7.5 ± 0.6

7.2 ± 1.2

7.3 ± 1.1#

7.5 ± 0.7#&

11.3 ± 1.6*&

9.5 ± 1.8*#&

9.1 ± 1.2*#&

Notes: * — to the control group, p < 0.001; # — to the analogous first age subgroups, p < 0.001; & — to the period preceding cholecystectomy, p < 0.001

 

In patients with FLD in the first age subgroup both among men and women, 76% and 71% of patients respectively were determined with signs of DOS, while in the second subgroup signs of DOS were determined in 55% of men and 52% of women, and in the third subgroup in 47 and 42%, respectively.

Using high-performance liquid chromatography, microbial markers were determined in blood, characterizing the quantitative composition of the microbiome of the parietal layer of the intestine of patients with developed FLD and patients without fatty changes in the liver. Since there were no significant changes between the parameters for men and women depending on gender, we combined these groups. Changes in the amount of parietal microflora in individuals with FLD relative to the control group were registered only years after CE (Table 10), etc. when obvious signs of FLD were present. Before CE, on average, in all patients there was a significant predomination of essential microflora over opportunistic one, as well as of anaerobic over aerobic. In a year after the intervention, in the group with FLD, the opportunistic microflora predominated over the essential one, and the aerobic microflora predominated over the anaerobic one. Of attention is the change in the distribution of obligate microflora after CE — in a year, the amount of lactobacilli in the parietal layer of the intestine prevailed over that of bifidobacteria, and the concentration of eubacteria significantly decreased. Also, the concentrations of fungi and viruses significantly increased in these patients. It is worth noting a decrease in the obligate microflora and an increase in the opportunistic one, also due to aerobic microflora in older people relative to younger ones.

 

Table 10. Parameters of Microbial Markers of Parietal Microbiome of Intestine Depending on Development of Fatty Liver Disease, M ± σ

Micro-organisms

Before Cholecystectomy

In a Year after Cholecystectomy

Control

Fatty Liver Disease

Control

Fatty Liver Disease

First Group

Second Group

Third Group

First Group

Second Group

Third Group

First Group

Second Group

Third Group

First Group

Second Group

Third Group

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

45–59 years

60–74 years

above 75 years

Obligate Anaerobes

Bifidobacterium

3292 ± 576

3156 ± 876

2563 ± 753#

3524 ± 1152

2667 ± 782#

2745 ± 893#

2530 ± 682&

2672 ± 738&

2276 ± 497#

1247 ± 528*&

1352 ± 631*&

1545 ± 752*#&

Eubacterium / Cl. Coocoides

9530 ± 1876

8231 ± 1572

7835 ± 1254

8635 ± 1618

8152 ± 1156

7529 ± 931#

8686 ± 952

7634 ± 857#

6670 ± 783&#

1958 ± 892*&

2841 ± 934*#&

2887 ± 1232*#&

Propioni-bacterium / Cl. Subterm

21924 ± 852

2195 ± 743

2284 ± 816

3164 ± 925

2263 ± 749#

2428 ± 673#

2478 ± 426

1844 ± 382##

1941 ± 375#

1246 ± 562*&

1683 ± 421*

1537 ± 397*#

Lactobacillus

2429 ± 1142

2662 ± 1271

2161 ± 928

2776 ± 1558

2844 ± 925

2531 ± 847#

2721 ± 659&

2532 ± 752

2308 ± 689#

1476 ± 246*&

1754 ± 584*#&

1868± 483*#&

Opportunists

Anaerobes

Bacteroides fragilis

271 ± 21

325 ± 34#

292 ± 62

256 ± 31

273 ± 43

281 ± 35

323 ± 52

448 ± 49

554 ± 53#

1089 ± 217*&

562 ± 72*&#

647 ± 84*&#

Fusobacterium / Haemophylus

131 ± 29

157 ± 21

141 ± 32*

142 ± 18

156 ± 24#

153 ± 22

161 ± 18

216 ± 23#

267 ± 28#

244 ± 26*&

193 ± 21*&#

221 ± 28*&

Eubacterium

24 ± 3

28 ± 12

25 ± 8

26 ± 9

28 ± 11

39 ± 13#

29 ± 11

38 ± 8#

47 ± 5#

28 ± 13*

30 ± 17*

34 ± 15*#

Peptostrepto- coccus anaero-bius (Гр. 1)

257 ± 36

308 ± 29#

277 ± 64

268 ± 42

289 ± 32

328 ± 28#

316 ± 33

425 ± 41#

526 ± 71#

976 ± 92*&

646 ± 81*&#

742 ± 78#*

Clostridium perfringens

956 ± 87

1147 ± 127

1032 ± 135#

882 ± 93

839 ± 94

952 ± 118#

1175 ± 174

1582 ± 231#

1648 ± 232#

936 ± 173*&

1251 ± 23*&#

1138 ± 198*&

Enterobacteria- cae (E. coli)

72 ± 9

86 ± 11

77 ± 14

69 ± 16

74 ± 12

77 ± 8

87 ± 13

118 ± 24#

146 ± 35#

73 ± 15

63 ± 14*&#

72 ± 12*

Bacillus cereus

139 ± 12

166 ± 19

150 ± 23

154 ± 25

167 ± 17

172 ± 19

170 ± 23

229 ± 36#

285 ± 31#

314 ± 26*&

219 ± 23*&#

251 ± 34*&##

Ruminicoccus

134 ± 14

160 ± 17

144 ± 32

342 ± 38

276 ± 29

293 ± 34

164 ± 27

220 ± 28#

273 ± 28#

1503 ± 134*&

499 ± 46*&#

574 ± 62*&#

Aerobes

Enterococcus

143 ± 16

153 ± 23

165 ± 27

171 ± 21

169 ± 24

158 ± 26

175 ± 21

211 ± 19#

313 ± 37#

1661 ± 518*&

5079 ± 1256*&#

5840 ± 1438*&#

Staphylococcus intermedius

256 ± 31

273 ± 36

291 ± 31#

239 ± 37

254 ± 35

237 ± 48

314 ± 39

376 ± 54#

552 ± 62#

1267 ± 568*&

1269 ± 382*&#

1459 ± 285*&#

Bacillus megaterium

2372 ± 242

2538 ± 251

2762 ± 416#

2287 ± 324

2612 ± 653#

2458 ± 821

2917 ± 962

3502 ± 749#

5247 ± 675#

3521 ± 482*&

4308 ± 671*&#

4954 ± 538*&#

Nocardia

273 ± 54

292 ± 37

314 ± 32#

258 ± 28

341 ± 35#

317 ± 34#

335 ± 45

402 ± 38

596 ± 63#

1326 ± 71*

548 ± 52*&#

630 ± 67*&#

Mycobacterium / Candida

152 ± 46

231 ± 28

352 ± 31#

187 ± 21

265 ± 24#

479 ± 56#

639 ± 83

724 ± 93

756 ± 81

1089 ± 148*&

659 ± 73*&#

756 ± 85*&#

Notes: * — to the control group, p < 0.001; # — to the analogous age subgroup, p < 0.001; & — to the period preceding cholecystectomy, p < 0.001

 

DISCUSSION

Evaluation of the anthropometric data permitted to determine the relationship between BMI and development of FLD in the long-term period after CE, which is more characteristic of older age groups, men and women over 60. We share the opinion of some authors that this is associated with impaired regulation of lipid and carbohydrate metabolism, which more quickly leads to formation of a persistent insulin resistance and hyperinsulinemia at an older age. With this, imbalance between consumption and utilization of lipids promotes their increased entry to the liver, where, due to decrease in oxidation processes in mitochondria and synthesis of very low density lipoproteins (characteristic of the older age) lipids accumulate in hepatocytes. A decreased number of patients over 75 with I and higher degree obesity has a simple explanation in the fact that most patients with this pathology seldom live to this age [18–20]. The results of the study showing age-related peculiarities of formation and course of FLD correlate with the data presented by some researchers about leveling out of the differences in the number of patients between men and women with cholelithiasis above 60; here, the difference is considerable until 45 when affected women 7 times outnumber men, but only twice at the age from 45 to 60 [1, 21, 22].

In the analysis of hemodynamic parameters and the autonomic status, of attention is a greater occurrence of sympathicotonia in patients with FLD of the first age group. It is known that in elderly and senile patients sympathetic regulation predominates with a general reduction of the autonomic tone. Here, due to age-related degeneration of the adrenergic synapses, the level of the autonomic regulation of the physiological system decreases [23]. At the same time, in individuals under 60, the autonomic regulation has a considerable effect on physiological systems and organs. Here, formation of insulin resistance leads to predomination of sympathetic regulation which facilitates spasm of Oddi sphincter [7, 24]. DOS (both insufficiency and spasm) impairs passage of bile, which, in turn, deranges the composition of the parietal microbiome of the intestine. Spasm of Oddi sphincter impairs regulation of the entry of bile acids which results in alterations of physiological circulation of bile and reduction of its bactericidal properties that provokes excessive microbial growth suppressing essential microorganisms [25, 26]. Since in the older age, sympathetic influence causing spasm of Oddi sphincter, diminishes, the regularity being more characteristic of individuals under 60 [12, 27–29].

Taking into account different mechanisms of formation of FLD in different age groups, it is possible to differentiate therapeutic tactics depending on predomination of the autonomic or metabolic disorders, which must increase the effectiveness of treatment.

CONCLUSIONS

1. In the pathogenesis of fatty liver disease developed in the long-term period (1 year) after cholecystectomy, the age-related differences are found: the lower autonomic regulation and the higher body mass in patients of the older group in comparison with patients of younger age.
2. Predomination of sympathetic regulation in patients under 60 is associated with dysfunction of Oddi sphincter that accelerates the formation of fatty liver disease.
3. In the long-term period after cholecystectomy in individuals with fatty liver disease developed within a year, significant changes in the microbial markers of the parietal microbiome of the intestine were determined that consisted in predomination of pathogenic microflora over essential one, and of aerobic microflora over anaerobic and in increase in the concentration of fungi and viruses.
4. In a year after cholecystectomy, in patients above 60 years reduction of obligate microflora and proliferation of opportunistic microflora, including due to aerobic microflora, were noted.

ADDITIONALLY

Funding. This study was not supported by any external sources of funding.

Conflict of interests. The authors declares no conflicts of interests.

Contribution of the authors: A. R. Ambartsumyan — concept and design of the study, writing the text; B. A. Chumak — processing of the material, writing the text; L. E. Deryagina — study concept and design, general guidance, text editing; S. S. Batskov — study design and text editing; E. D. Pyatibrat — concept and text editing. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work.

Финансирование. Авторы заявляют об отсутствии внешнего финансирования при проведении исследования.

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

Вклад авторов: Амбарцумян А. Р. — концепция и дизайн исследования, написание текста; Чумак Б. А. — обработка материала, написание текста; Дерягина Л. Е. — концепция и дизайн исследования, общее руководство, редактирование текста; Бацков С. С. — дизайн исследования и редактирование текста; Пятибрат Е. Д. — концепция и редактирование текста. Все авторы подтверждают соответствие своего авторства международным критериям ICMJE (все авторы внесли существенный вклад в разработку концепции, проведение исследования и подготовку статьи, прочли и одобрили финальную версию перед публикацией).

About the authors

Aleksandr R. Ambartsumyan

Gas Industry Insurance Company

Email: ambartsumyan_al@mail.ru
ORCID iD: 0000-0001-9689-6929
SPIN-code: 5403-8181

MD

Russian Federation, Saint-Petersburg

Boris A. Chumak

Kirov Military Medical Academy

Email: borchum07@yandex.ru
ORCID iD: 0000-0001-5310-0812
SPIN-code: 1973-6961

MD, Cand. Sci. (Med.)

Russian Federation, Saint-Petersburg

Larisa E. Deryagina

V. Ya. Kikot Moscow University of the Ministry of Internal Affairs of the Russian Federation

Author for correspondence.
Email: lderyagina@mail.ru
ORCID iD: 0000-0001-5522-5950
SPIN-code: 6606-6628

MD, Dr. Sci. (Med.), Professor

Russian Federation, Moscow

Sergey S. Batskov

The Nikiforov Russian Center of Emergency and Radiation Medicine

Email: rokotyanskaya.ea@mail.ru
ORCID iD: 0000-0002-8196-3831
SPIN-code: 8914-2094

MD, Dr. Sci. (Med.), Professor

Russian Federation, Saint-Petersburg

Elena D. Pyatibrat

Kirov Military Medical Academy

Email: a5brat@yandex.ru
ORCID iD: 0000-0003-4070-5374
SPIN-code: 9463-7160

MD, Dr. Sci. (Med.)

Russian Federation, Saint-Petersburg

References

Supplementary files