“L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety”, Ministry of Health of Ukraine, Kyiv, Ukraine

Abstract. Objective: to substantiate rational criteria of diagnostics and methods of differentiated therapy based on the study of the structure and features of the course of clinical syndromes of hepatobiliary system impairment and oxidative stress in acute and chronic pesticide intoxications.
Material and methods. Frequency and features of hepatobiliary system impairment in 308 agricultural workers with pesticide intoxications in the acute and long-term periods were performed. Among them, there were 238 patients with acute poisoning: 162 — with herbicides based on 2,4-dichlorophenoxyacetic acid (2,4-D), 62 — with organophosphorus compounds (OPC), 14 — with synthetic pyrethroids (SP) and 70 — with chronic pesticide intoxication (CPI). Clinical and instrumental, biochemical and statistical methods of research were used.
Results and conclusions. Along with neurological disorders, the toxic liver damage was observed in 35,8 % of cases of acute poisoning with herbicides based on 2,4-D, in 51,6 % of cases of OPC poisonings, and in most cases of SP poisonings and CPI. Among clinical manifestations of toxic hepatitis, the prevalence of the cytolytic syndrome and hepatosteatosis, less often in combination with the cholestatic or hepatodepressive syndrome, was observed. The differentiated use of antioxidants — α-lipoic and ursodeoxycholic acid — in the complex treatment of pesticide intoxications was substantiated.
Key words: pesticides, acute and chronic intoxications, hepatobiliary system, oxidant-antioxidant disorders, α-lipoic and ursodeoxycholic acid.

The pathology of the hepatobiliary system is still a serious worldwide socioeconomic health problem occupying a significant place in the structure of the overall disease burden [1—6]. Liver diseases of both viral and chemical aetiology are often accompanied by the development of not only hepatosteatosis, steatohepatitis, but also cirrhosis, and lead to a decrease in professional capacity and to disability [1, 3, 4, 5].

Taking into account an intense use of chemical plant protection agents in agriculture, there are both acute and chronic pesticide intoxications still registered, clinical pattern of which, along with neurological disorders, are presented with toxic damage of the liver, which is the organ that provides the main processes of detoxification.

If the neurotoxic effects of pesticides, including OPC, herbicides based on 2,4-D, SP, are quite well studied both in the experiment and in the clinical settings, their hepatotoxic and pro-oxidant actions were studied mainly in experiment in recent years [7–8, 13–20]. Thus, in case of intragastric effects of such OPCs as malathion in doses of 42.5 mg/kg and 85 mg and diazinon (20 mg/kg), an increase in the average body weight of rats, development of pericentrolobular vasodilation and diffuse macrovesicular steatosis, and in some cases, foci of necrosis and granulovascular dystrophy of the liver were observed at lower doses of malathion (42.5 mg/kg) and diazinone (20 mg/kg) after 14 and 35 days [9].

A study of the acute toxic effect of the OPC agent, fenthion, on the liver of rats showed that if its LD₅₀ for rats in case of oral administration is 298 mg/kg, a significant increase in the activity of ALT, AST and GGT and a development of moderate histological abnormalities in liver cells, especially the central lobular zone with the activation of Kupffer cells, were observed in as little as 24 hours after intragastric administration of 25 and 50 mg/kg [13]. And a very interesting fact is that the blood levels of acetylcholinesterase (ACh-E) and butyrylcholinesterase (BCh-E) were still within normal limits. 24 hours after the administration of 75 and 100 mg/kg of fenthion, neurologic disorders, more pronounced activation of ALT, AST and GGT, significant inhibition of ACh-E and BCh-E, and also clear histopathological and morphological changes in the liver with the development of steatosis were observed [13].

In recent years, a number of experimental studies showed that acute and chronic OPC intoxication is accompanied by a destructive effect on the intracellular liver structure with the subsequent development of fatty degeneration [14–19]. Thus, when exposed to 14 mg/kg (1/10 LD₅₀) of dimethoate insecticide, the liver of white mice presented with severe cellular infiltration, vasodilation and increase in the amount of fat in hepatocytes [14]. At a larger dose of dimethoate — 28 mg/kg (1/5 LD₅₀), more pronounced cellular infiltration, hepatocyte hypertrophy with vacuolation and development of diffuse macrovesicular steatosis were observed [14].

A number of experimental studies established both hepatotoxic and pro-oxidant effects of OPC [9–12, 17–19]. The development of oxidative stress with inhibition of the antioxidant system under the influence of diazinon was observed during the experiment [9–12]. An activation of the antioxidant system and the hepatoprotective effect of vitamin E and selenium in rats exposed to malathion [18], as well as a decrease in the intensity of pro-oxidant and morphological disorders in the liver of rats with malathion intoxication exposed to α-lipoic acid [19], a decrease in the intensity of oxidative stress and an activation of the antioxidant system under the influence of catechin and quercetin in rats with chlorpyrifos intoxication [20] were observed.

It was found that intragastric administration of 8, 10, 12 and 20 mg/kg of diazinon in rats was also accompanied by the development of oxidative stress and an increase in the level of malondialdehyde (MDA) from 5.99 mmol/L when administering 8 mg/L to 10.23 mg/L when administering 20 mg/kg [36].

In addition, glutathione peroxidase activity decreased almost threefold and superoxide dismutase (SOD) activity decreased more than twofold with inhibition of lactate dehydrogenase and acetylcholinesterase activity, which is indicative of a decreased synthetic liver function; and at the same time, at a higher dose of diazinon, hyperlipidemia increased: the blood serum content of total lipids, triglycerides, cholesterol and low-density lipoproteins increased almost 2,5-fold, and also histological disorders in skeletal muscles and heart muscle [36]. The vitamin E protective effect in case of diazinon-induced hepatotoxicity was also observed [37]. In the experiment on rats, hepatotoxic effects with hyperlipidemia in rats exposed to cypermethrin were also observed [38].

Experimental studies on the toxic effect of herbicides based on 2,4-D detected their membrane toxicity effects, and it was established that 2,4-D interact predominantly with polar groups of membrane lipids, which is due to their anionic properties [24].  The main mechanism of the 2,4-D toxic effect on warm-blooded animals involves the separation of oxidation and phosphorylation processes, which leads to disturbances in energy metabolism with dissociation of dehydrogenases isoenzymes, accumulation of lactic acid and development of energy deficiency [24, 25]. The bioenergetic imbalance is accompanied by a disturbance of cell membrane resistance and ion channel functions, electrical potentials of muscle and nerve cells with structural and ultrastructural degenerative changes [24]. Watt B. E et al. [24] consider the disturbances of the metabolism of acetyl-CoA, the cycle of tricarboxylic acids and β-oxidation of fatty acids to be one of the main directions of the 2,4-D toxic effect, which can be responsible for hepatotoxic and steatogenic effects in the body. This can be facilitated by the detected morphological changes in mitochondria and lysosomes of hepatocytes under the acute effect of 2,4-D [26, 27, 34], as well as the activation of pro-oxidant processes [22, 28, 29, 34].

Given the unique properties of 2,4-D herbicides, such as chemical stability and high lipophilicity, which contribute to its accumulation and retention in the body [21, 33], an attempt was made to study the effect of non-toxic doses of 2,4-D herbicide on the dynamics of animal body weight [32]. An experiment on rats fed 2,4-DA herbicide in a concentration of 0.015 mg/L (0.5 MAC) with drinking water within 6 weeks detected a body weight gain in comparison with the control group in as little as a week, which was significantly increased in 6 weeks as well. In addition, the weight of epididymal fat (4.8 g in the control group and 6.4 g in the experimental one) was almost 1.5 times greater, which to some extent speaks for the 2,4-D obesogenic effects, the formation mechanisms of which require further research. SP toxic effects are also primarily associated with the development of neurological disorders, while some studies mention hepatotoxic, nephrotoxic and pro-oxidant effects [34].

Features of toxic hepatitis development under the influence of OPC, herbicides based on 2,4-D, SP and chronic effects of pesticide complex in workers are insufficiently studied and described only in single studies with no focus on clinical syndromes. The contribution of the disorder of oxidant-antioxidant processes to the development and progression of the hepatobiliary system disturbances in case of pesticide intoxication requires further research. Rational diagnostics criteria and effective differentiated treatment methods depending on the prevailing clinical syndrome are not sufficiently substantiated. The study of the toxic hepatitis outcomes is of particular interest: the frequency of hepatosteatosis, steatohepatitis and cirrhosis, as well as the development of criteria to predict their development.

Objective of the study. To substantiate rational criteria of diagnostics and methods of differentiated therapy based on the study of the structure and features of the course of clinical syndromes of hepatobiliary system disturbance and oxidant-antioxidant processes in acute and chronic pesticide intoxications.

Materials and study methods. 236 workers of agriculture with acute pesticide poisoning were examined over time: 162 — with herbicides based on 2,4-D amine salt, 60 — with OPC, 14 — with SP, and 70 — with chronic pesticide intoxication (CPI) due to the long-term occupational exposure to a complex of pesticides. As a control, 30 practically healthy agricultural workers were examined, who did not come into contact with toxic substances during the work.

All cases of acute poisoning with 2,4-D, OPC and SP occurred in agricultural workers due to gross violations of hygienic regulations for their use. The occupational structure of patients with acute 2,4-D poisoning was represented by field beet growers. Among 60 patients with OPC poisoning, there were 36 grape growers, 9 cattlemen, 8 gardeners, 3 machine operators and 4 handymen.  Among 14 cases of SP poisoning —– 8 gardeners and 6 handymen. Age of patients with acute pesticide poisoning ranged from 28 to 58 years (mean — 38.2 ± 0.9 years), and patients with CPI — from 32 to 57 years (mean — 48.3 ± 0.6). The mean age of the patients from the control group is 37.8 ± 2.2 years.   The occupational structure of 70 patients with CPI was represented by 16 heads and workers of chemical pesticide stores (22.3 %), 6 tobacco growers (8.6 %), 25 machine operators (35.7 %), 18 gardeners and grape growers (25.7 %) and 5 disinfectors (7.1 %). The work experience of patients with CPI ranged from 7 to 36 years (mean — 18.8 years).

Of 60 cases of OPC poisoning, in 13 (21.7 %) cases it occurred due to exposure to carbophos, in 8 cases (13.3 %) — due to dichlorvos, in 3 cases (5 %) — due to phosalone and in 36 cases (60 %) — due to dimethoate. Of 14 cases of acute SP poisoning, in 9  patients it occurred due to poisoning with Decis (the active ingredient is deltamethrin), in one case — due to Arrivo (cypermethrin), in 3 cases — due to sumicidin (fenvalerate) and in one case — due to Karate (lambda-cyhalothrin).

The object of this study is the hepatobiliary system disturbance in agricultural workers with acute and chronic pesticide intoxications. The subject is syndromes of the hepatobiliary system disturbance and oxidant-antioxidant disorders with substantiation of informative diagnostics methods and differentiated application of antioxidants.

The general clinical methods were used to examine the patients: examination, questioning, study of medical documentation (outpatient record data, sanitary and hygienic characteristics of working conditions, industrial accident report, toxicological studies on the content of pesticides in the working zone air and in the blood of victims), anthropometric data, abdominal ultrasound, as well as biochemical examinations. To exclude the viral aetiology of hepatitis, a determining of serological markers of viral hepatitis and PCR were conducted to detect the virus DNA. Hemochromatosis, Wilson’s disease etc. were also excluded.  When evaluating the functional state of the liver, the activity of alanine (ALT), aspartate (AST) aminotransferases, alkaline phosphatase (AP), γ-glutamyltranspeptidase (GGTP) (synonym: γ-glutamyltransferase — GGTP), the content of bilirubin (BIL), albumin (A), globulin (Gl), bile acids (BA), cholesterol (CH), fibrinogen, prothrombin, C-reactive protein (C-RP) and indices of thymol test were determined using uniform standard methods [39, 40]. Taking into account that in experimental animals intoxication with OPC, herbicides based on 2,4-D and SP is accompanied by activation of lipid peroxidation processes [10, 11, 23, 26, 29, 38], the state of oxidative stress was evaluated according to the blood level of malondialdehyde (MDA) and its interaction with thiobarbituric acid [39]. To assess the state of antioxidant protection, the activity of superoxide dismutase (SOD) was determined by the Mistra method in the modification by O. P. Makarevych et al. [41], as well as catalase activity and ceruloplasmin level [40]. To assess the severity of metabolic endotoxicosis, the content of medium-molecular peptides (MMP) was determined at a wavelength of 254 nm and 280 nm [43]. A differentiated diagnosis of the main syndromes of the hepatobiliary system disturbance was determined on the basis of a comprehensive clinical and biochemical and ultrasound study in accordance with [1, 4, 44]. Thus, the cytolytic syndrome, which is the most important syndrome, the presence, severity and aetiology of which determine the entire strategy of the treatment of acute hepatopathy or chronic toxic, viral hepatitis or hepatitis of other aetiology, which develops due to increased permeability of membranes and degeneration of hepatocytes, was established with an increase of ALT, AST and GGTP activity in the blood serum.

The degree of acute hepatopathy or chronic toxic hepatitis activity was established mainly according to the blood level of ALT: If the blood level of ALT is increased more than 2-fold, the activity is low (I degree); if the level is increased 3–10-fold, the activity is moderate (II degree). Cases of pronounced activity (ІІІ degree) with an increase of the ALT level more than 10-fold were not observed.

Syndrome of intrahepatic cholestasis indicative of basolateral and canalicular membrane permeability disorder, a disturbance of the cytoskeleton of hepatocytes and tubules, as well as metabolic and bile acid compound disturbances [1–6, 44, 45] was established with increased blood levels of AP, GGTP, conjugated and total bilirubin, free bile acids (BA), and triglycerides. Hepatodepressive (hepatoprive) syndrome or syndrome of decreased synthetic liver function usually associated with decreased liver detoxification function [1–6] was established in case of decreased blood levels of albumin with relatively increased blood level of high-molecular-weight proteins — γ-globulins, as well as decreased level of prothrombin, fibrinogen, cholesterol, AChE, ceruloplasmin and increased level of thymol test. The presence and severity of steatosis was established on the basis of liver ultrasound data with elastography. The degree of steatosis severity was determined by the ultrasound attenuation ratio (M. Sasso et al. 2010, 2017) [46, 48]: S1 — 2.20-2.29 dB/cm (mild steatosis usually involving 5 to 33 % of hepatocytes); S2 — 2.30–2.90 dB/cm (moderate steatosis involving 33-66 % of hepatocytes); S3 — over 2.90 dB/cm (pronounced steatosis involving more than 66 % of hepatocytes). Steatohepatitis or non-alcoholic steatohepatitis was established with an additional increase of liver size and an increase in the level of ALT, AST, GGTP.

Statistical processing was carried out using parametric statistics methods with standard programs taking into account the basic principles of the study of statistical methods in clinical trials [42]. All examinations were carried out with the consent of the patients and consistent with ethical standards.

Results and their discussion. All examined patients with acute poisoning with herbicides based on 2,4-D, OPC and SP, and also with CPI had the following neurological disorders prevailed in their clinical picture: toxic encephalopathy, asthenovegetative syndrome, less often in combination with vegetative and sensory polyneuropathy of the extremities. Studies showed that patients with acute and chronic pesticide intoxications often develop toxic liver damage (according to ICD-10), which in acute exogenous intoxications is defined as acute hepatopathy and toxic hepatitis in chronic intoxications [1, 4, 45]. Patients with the hepatobiliary system disturbance complained of general weakness, decreased appetite, aching pains or discomfort in the right hypochondrium, bitterness in the mouth, nausea, sometimes vomiting, and bloating. In case of acute poisoning with herbicides based on 2,4-D, complaints of pain in the right hypochondrium, nausea, bitterness in the mouth appeared during the first week, while signs of increased liver density and the cytolytic syndrome with increased levels of ALT, GGTP in some cases were observed later — 20–30 days after poisoning. In acute poisoning with OPC and SP neurological disorders prevailed within the first 2 weeks, then there was pain in the right hypochondrium, nausea, bitterness in the mouth, increased liver density, less often — liver enlargement with the development of the cytolytic syndrome, less often — cholestasis syndrome in combination with hepatodepressive syndrome.

Table 1 shows that in case of acute poisoning with herbicides based on 2,4-D, toxic liver damage was observed in 58 of 162 patients (35.8 %); in case of acute poisoning with OPC — in 32 of 62 (51.6 %); in case of acute poisoning with SP — in 9 of 14 (64.2 %) and in case of chronic pesticide intoxication — in 59 of 70 (84.2 %).

Table 1. Frequency of toxic damage of the hepatobiliary system in acute and chronic pesticide intoxications.

Groups of examined patients	Number of patients	Frequency of the hepatobiliary system toxic damage in pesticide intoxications
		total	%
Acute poisoning with herbicides based on 2,4-D	162	58	35.8
Acute poisoning with organophosphorous compounds	62	32	51.6
Acute poisoning with synthetic pyrethroids	14	9	64.2
Chronic pesticide intoxication	70	59	84.2

If acute poisoning with herbicides based on 2,4-D mainly caused 1,5––2-fold increase of the ALT level, which corresponded to the cytolytic syndrome of the I degree, a poisoning with OPC, SP, and especially chronic intoxication due to prolonged exposure to a complex of pesticides often caused 2–4-fold increase of the ALT levels (cytolysis of the II degree). If the average ALT level in case of poisoning with herbicides based on 2,4-D increased to 0.78 ± 0.02 μmol/L (p < 0.05), in case of poisoning with OPC, it increased to an average of 0.97 ± 0.06 μmol/L (p < 0.05), in case of poisoning with SP — up to 0.92 ± 0.9, and in case of CPI — up to 0.98 ± 0.04 (p < 0.05, Table 2). The AST level increase in both acute and chronic intoxications was significantly less frequent, while an increase of GGTP levels was more frequent, especially in case of poisoning with OPC and CPI, in which the average GGTP level increased to 7.26 ± 0.02 and 8.38 ± 0.02 mmol/(h.L), respectively, (p < 0.05, Table 2). The cytolytic syndrome in acute poisoning with herbicides based on 2,4-D and SP was observed less frequently and was less prominent, while in case of poisoning with OPC, it was observed in 93.7 % of cases, and in CPI, it was observed in all cases of chronic toxic hepatitis (Table 3), and in about half of the cases with the cytolysis activity of the II degree.

Table 2. The main biochemical indicators in patients with toxic liver damage in case of pesticide intoxications (M ± m).

Note: * the difference is statistically significant in comparison with the control group (p <0.05)

 

Table 3. Frequency of the main syndromes of the hepatobiliary system toxic damage in case of pesticide intoxications.

 

Less frequently, in both acute and chronic intoxications, the cytolytic syndrome was combined with intrahepatic cholestasis and hepatodepressive syndromes with a decrease in the synthetic and detoxification liver functions (Table 3). Thus, when poisoning with herbicides based on 2,4-D, the syndrome of intrahepatic cholestasis with a slight increase in the levels of AP, bilirubin and free bile acids was observed only in 13.8 %, and hepatodepressive syndrome with a slight decrease in the level of fibrinogen and prothrombin index without a significant decrease in the level of albumins was observed only in 10.3 %. However, in cases of poisoning with OPC, SP, and especially in CPI, cholestasis and hepatodepressive syndromes in the background of the cytolytic syndrome were observed in more than 20 % of cases (Table 2).

The study of the oxidative and antioxidant system state in case of pesticide intoxication showed the development of oxidative stress with a statistically significant increase in the average level of MDA in both acute and chronic intoxications, especially in case of acute poisoning with OPC and CPI (an increase of the average MDA level was almost 3-fold (Table 4).

Table 4. Indices of the oxidative and antioxidant system in patients with toxic damage of the hepatobiliary system in case of pesticide intoxications (M ± m).

Note: * the difference is statistically significant in comparison with the control group.

 

At the same time, there was a decrease in the level of antioxidant system indicators, especially in case of poisoning with OPC and CPI, in which the level of SOD, ceruloplasmin and SH-GROUPS was significantly decreased (p < 0.05, Table 4). Primarily, in patients with a combination of cytolytic, cholestatic and hepatodepressive syndromes, the formation of metabolic endotoxicosis was observed with an increase in the MMP blood levels at a wavelength of of both 254 nm and 280 nm (Table 2). Higher levels of MMP were observed in case of poisoning with OPC and CPI — 0.288 ± 0.03 and 0.286 ± 0.03, respectively, at a wavelength of 254 nm (p < 0.05) and 0.296 ± 0.04 and 0.326 ± 0.02, respectively, at a wavelength of 280 nm (p < 0.05, Table 2).

As early as the first 10 days after acute poisoning with pesticides, especially OPC and SP, there was an increase in the liver structure density observed by ultrasonography with elastography, which was shown to intensify during examination in 1 and 3 years, which indicated the hepatosteatosis development.  If in healthy individuals the ultrasound attenuation coefficient during liver elastography averaged 1.2 ± 0.02 dB/cm, in patients with 2,4-D poisoning it increased to 2.28 ± 0.03 dB/cm (p < 0.05) in 20–30 days, with SP poisoning — up to 2.22 ± 0.09 dB/cm (steatosis of mild degree), with OPC poisoning — up to 2.42 ± 0.04 dB/cm (p < 0,05), and in case of chronic toxic hepatitis in patients with chronic pesticide intoxication — up to 2.66 ± 0.06 dB/cm (p < 0.05), which according to M. Sasso et al. [46, 48] corresponds to the development of moderate steatosis involving 33–66 % of hepatocytes.

The study of the incidence of hepatobiliary system disturbance in acute and chronic pesticide intoxications with the determination of liver damage syndromes and development of oxidative stress with simultaneous suppression of the antioxidant system state and hepatosteatosis made it possible to substantiate the differentiated use of antioxidant therapy in the complex treatment of patients with pesticide intoxications. In people with prevailing the cytolytic syndrome with a high blood level of MDA and hepatosteatosis development, the use of α-lipoic acid, which is known to be an active antioxidant, participate in the regulation of lipid and carbohydrate metabolism, have a pronounced detoxification effect and improve liver function, was substantiated. Complex detoxification therapy of all patients with acute and chronic pesticide intoxications, both in patients from the control and the main group, was carried out according to the methodical recommendations which we had developed earlier [46]. Simultaneously with complex therapy, the patients from the main group were additionally prescribed to get intravenous infusions of α-lipoic (thioctic) acid (600 mg per day) for 2–3 weeks, followed by a long-term administration per os of 600 mg per day). Inclusion of α-lipoic acid to the treatment complex contributed to an earlier improvement of liver functions, a decrease of the cytolytic syndrome severity, a decrease of the blood levels of MDA (p < 0.05), and an increase of the antioxidant system indices: SOD, ceruloplasmin and SH-groups (p < 0,05). The results of the α-lipoic acid efficacy evaluation in acute poisoning with herbicides based on 2,4-D are set forth by us earlier [47].

Treatment complex of the patients with acute and chronic intoxications, who had the cytolytic syndrome combined with intrahepatic cholestasis syndrome, included infusions of ursodeoxycholic acid at a dose of 13–15 mg/kg/day within 2–3 weeks. Ursodeoxycholic acid has choleretic, antioxidant, hepatotrophic, detoxification, immunomodulating, anti-inflammatory and anti-fibrogenic effects, and we, therefore, found it expedient to use it to treat liver damages in patients with pesticide intoxications who had the cytolytic syndrome in combination with cholestasis syndrome. Patients, who had the cytolytic syndrome combined with cholestasis syndrome and hepatodepressive syndrome, were additionally prescribed to get infusions of hepatoprotector Essentiale N (250 mL/day) for 2–3 weeks with a transition to a long-term intake of 300 mg of Essentiale Forte N in capsule per os. The active ingredient of the drug is the so-called essential phospholipids, which are a highly purified fraction of phosphatidylcholine.  Essential phospholipids promote the regeneration of cell membranes and hepatocytes, increase the detoxification capacity of the liver and thus normalise its function. Analysis of the results of treatment with the inclusion of ursodeoxycholic acid and Essentiale N showed a significant increase in the treatment effectiveness in comparison with the control group. The inclusion of ursodeoxycholic acid monotherapy to the complex treatment contributed to a decrease of the AP level in case of poisoning with OPC from 132.24 ± 5.18 to 98.12 ± 4.92 units/L, and in case of chronic pesticide intoxication — from 138.16 ± 4.82 to 88.16 ± 5.04 units/L (p<0.05), and also normalised the blood levels of GGTP and free bile acids (p<0.05).

Additional inclusion of Essentiale N hepatoprotector caused not only the regression of cytolysis and cholestasis syndromes but also significantly reduced the hepatodepressive syndrome severity. Patients, who were additionally prescribed to use Essentiale N, showed a normalisation of blood content of AP, GGTP, bile acids, bilirubin, thymol test (p < 0.05), and also a statistically significant increase of the level of albumin, prothrombin index and fibrinogen (p < 0.05), which is indicative of the restoration of protein-synthetic and the improvement of detoxification functions of the liver.

Thus, toxic liver damage is common both in acute poisoning with OPC, herbicides based on 2,4-D and SP, and especially in chronic intoxications caused by prolonged exposure to a complex of pesticides. The prevailing syndrome in the clinical picture of acute pesticide intoxications is the cytolytic syndrome of liver damage, the manifestation of which in some cases is delayed or indicates the need to search for more sensitive biomarkers for its diagnostics. The structure of the main toxic hepatitis syndromes in case of chronic pesticide intoxications is presented with the cytolytic syndrome (often with the II degree of activity) in all cases. Both in acute, and especially in chronic pesticide intoxications, the cytolytic syndrome in almost 20 % of cases is combined with intrahepatic cholestasis syndrome and in 20–25 % of cases — with hepatodepressive syndrome. It was found that toxic liver damage in case of pesticide intoxications is accompanied by hepatosteatosis development, oxidative stress activation with inhibition of the antioxidant system components and metabolic endotoxicosis development, which allowed to substantiate the differentiated application of antioxidants (α-lipoic acid, ursodeoxycholic acid and hepatoprotector Essentiale N).

 

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