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American Journal Of Biomedical Science & Pharmaceutical Innovation    
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VOLUME 04 ISSUE 03 PAGES: 24-35 

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ABSTRACT 

Steatohepatitis is hepatic steatosis with inflammation and, in some cases, hepatocyte balloon degeneration and 

fibrosis [1]. Steatohepatitis is a form of non-alcoholic fatty liver disease (NAFLD), which includes a wide range of 

conditions: from non-alcoholic steatosis (NAS) - fat deposition in the liver of more than 5% of the parenchymal mass 

without signs of damage to hepatocytes to non-alcoholic steatohepatitis (NASH), which progresses with development 

fibrosis, cirrhosis and, in some patients, hepatocellular carcinoma [1]. The prevalence of steatohepatitis in the pediatric 

population, according to various sources, varies greatly. Thus, the recommendations of the North American Society 

of Pediatric Gastroenterologists, Hepatologists and Nutritionists (NASPGHAN) indicate that hypertransaminasemia 

occurs in 29-38% of obese children aged 2-4 years [1]. According to A. Sahota et al. [2], NASH was found in 12% of obese 

and overweight children. The joint recommendations for the diagnosis, treatment and prevention of obesity in 

children and adolescents of the Russian Association of Endocrinologists, the Russian Society for the Prevention of 

Non-Infectious Diseases, and the Association of Pediatric Cardiologists of Russia note that NASH is diagnosed in 12-

26% of obese children and adolescents [3]. Obesity and overweight currently affect 25-30% of school-age children [4]. 

The situation is almost the same for preschool children. The COSI (Childhood Obesity Surveillance Initiative) study, 

conducted under the WHO program in Moscow in 2017-2018, summing up the dynamics of body weight for the entire 

preschool period, showed that among children aged 7 years, 27% of boys were overweight and 22% of girls, and obesity 

- in 10 and 6%, respectively [5].  Another Russian study assessing the physical development of children of middle and 

school age [6] also demonstrated a significant prevalence of obesity and overweight in this age group in Russian 

regions. Thus, at 11 years of age, obesity in boys was recorded in 18.6% of cases, in girls - in 9.2%, and excess body weight 

  Research Article 

 

STEATOHEPATITIS IN OBESITY CHILDREN 

Submission Date: March 07, 2024, Accepted Date:  March 12, 2024,  

Published Date: March 17, 2024  

Crossref doi: https://doi.org/10.37547/ajbspi/Volume04Issue03-04 

 

 

Garifulina Lilya Maratovna  
Candidate of Medical Sciences, Associate Professor of the Department of Pediatrics, Faculty of Medicine 

SamSMU, Uzbekistan 

 

Turaeva Dilafruz Kholmurodovna 
Assistant of the Department of Pediatrics, Faculty of Medicine SamSMU, Uzbekistan 

 

Norkulova Aziza Rustamovna 
RCEMPNC SF pediatrician, 2nd children's department, Uzbekistan 

 

Journal Website: 

https://theusajournals.

com/index.php/ajbspi 

Copyright: Original 

content from this work 

may be used under the 

terms of the creative 

commons attributes 

4.0 licence. 

 

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- in 15.4 and 14.3%, respectively. At the age of 15, obesity was detected in 10% of cases among boys, in 3.6% of girls, and 

overweight in 11.5 and 10.5% of cases, respectively [6]. Based on these data, it can be assumed that the incidence of 

NASH in the pediatric population varies from 0.5 to 3%. It should be noted that the prevalence of obesity, and with it 

NAFLD, including NASH, is increasing throughout the world due to modern negative trends in the diet and physical 

activity of children [7]. 

KEYWORDS 

Population, hepatocytes, non-alcoholic steatosis (NAS), non-alcoholic fatty liver disease (NAFLD). 

INTRODUCTION

Pathogenesis 

The pathophysiology of molecular abnormalities in 

NASH is complex and multifactorial. Metabolic 

imbalances that result in fat deposition in the liver are 

associated with three mechanisms (see figure) [8]: 

an increase in the amount of free fatty acids entering 

hepatocytes due to increased dietary fat intake or 

quantitative/qualitative disturbances of the intestinal 

microbiome; 

• an increase in the supply of free fatty acids to 

hepatocytes from the non-esterified pool, the source 

of which is white adipose tissue; 

• activation of de novo lipogenesis in the liver, the 

cause of which is associated with excess carbohydrates 

and/or hyperinsulinemia due to the resistance of 

adipose tissue to insulin. 

Accumulation of triglycerides and free fatty acids in 

hepatocytes occurs when these processes are not 

compensated by increased production of very low-

density lipoproteins in the liver [8]. It is generally 

accepted that lipotoxicity is associated with the 

accumulation in hepatocytes not of triglycerides, but 

of free fatty acids and their metabolites [8], leading to 

oxidative stress and subsequent damage to 

intracellular structures (mitochondria, endoplasmic 

reticulum). These changes cause a cascade of 

reactions, including the release of reactive oxygen 

species, IL-6, -10, -18, TNF-α, IFN-γ by hepatocytes and 

the recruitment of immune cells (plasmocytes, 

lymphocytes) [8]. 

These processes culminate in hepatocyte damage, 

progressive inflammation, programmed cell death 

(apoptosis), and fibrotic remodeling of the liver 

through collagen deposition from activated stellate 

cells [8]. 

In recent years, the pathogenesis of NAS and NASH has 

been linked to changes in the gut microbiota that lead 

to bacterial translocation, especially of a highly 

immunoreactive Gram-negative cell wall component 

called lipopolysaccharide (LPS), into the systemic 

circulation, which further enhances the inflammatory 

process by activating macrophages and Kupffer cells. 

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VOLUME 04 ISSUE 03 PAGES: 24-35 

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It has been established that changes in the intestinal 

microbiota in patients with NAFLD are associated with 

the genes K01470, K01961, K07258 and are manifested 

by disruption of the pathways of arginine and proline 

metabolism, fatty acid synthesis and polysaccharide 

biosynthesis and metabolism [9]. 

In addition, these three functional genes were 

associated with significant disturbances in the 

intestinal microbiome - a decrease in the number of 

Bacteroides, Bifidobacterium, Ruminococcus and an 

increase in Prevotella, which shows the possibility of 

the influence of disturbances in the intestinal flora on 

changes in lipid metabolism due to differential 

expression of genes contributing to the pathogenesis 

of NAFLD, including. h. NASH [9].  Overfeeding of 

children in infancy leads to excess body weight in the 

future, which, in turn, can predetermine the 

development of NAFLD. An experimental study in rats 

showed that overfeeding rats aged 3-13 weeks caused 

excess glucocorticoids through activation of the 

enzyme 11β-HSD1 (11β-hydroxysteroid dehydrogenase 

type 1) in the liver, which, in turn, activated de novo 

hepatic lipogenesis through glucocorticoids. 

receptors, which led to lipid accumulation in the liver, 

increased the risk of NAFLD in adulthood [10]. 

In research, great importance is given to the analysis of 

genetic predisposition to obesity and NASH. A 

significant role in the occurrence of NASH belongs to 

the PNPLA3 gene, encoding the triacylglycerol lipase 

protein, which is involved in lipid metabolism and 

promotes the accumulation of lipid molecules in 

hepatocytes; an association of PNPLA3 polymorphism 

with increased ALT levels and a more frequent 

occurrence in obese children of different ages with 

metabolic syndrome has been established [11]. The 

TM6SF2 gene, encoding superfamily 2 transmembrane 

protein 6, promotes the formation of excessive 

amounts of very low density lipoproteins in 

hepatocytes, which leads to the accumulation of 

triglycerides in liver cells [12]. The role of the AKR1D1 

gene, encoding steroid 5β-reductase, variants of which 

increase the accumulation of triglycerides in 

hepatocytes, insulin sensitivity and glycogen synthesis 

by increasing de novo lipogenesis and reducing β-

oxidation, activating hepatocyte inflammation, has 

also been noted [13]. There is an association between 

the MTHFR 677CT gene variant and the level of 

homocysteine as a component of oxidative stress in 

patients with NAFLD [14]. Other genes that are 

important in the development of NASH and 

progression to steatofibrosis have also been identified 

[12]. 

The role of vitamin D in the pathogenesis of NAFLD is 

being studied. In the work of M. Kong et al. It has been 

demonstrated that a high-fat diet deficient in vitamin D 

interferes with the enterohepatic circulation of bile 

acids, leading to NASH [15]. It has also been shown that 

vitamin D deficiency can increase adipose tissue 

dysfunction and, in particular, cause an increase in the 

production of cytokines (TNF-α, IL-1β, IL-6), which 

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contributes to the progression of NAFLD  [16]. It was 

shown that in children with NAFLD, significant liver 

fibrosis (stage ≥ 2 by ultrasound) was detected in 29% 

with vitamin D deficiency (serum 25(OH)D 

concentration - 21-30 ng/ml) and in 17% with normal 

vitamin levels [17]. 

Diagnostics 

Laboratory diagnostics 

Diagnosing NASH in children, as well as NAFLD in 

general, is not difficult. According to the 

recommendations of ESPGHAN (2012), the 

examination and differential diagnosis plan for children 

with NAFLD should include the following laboratory 

tests [4]: 

• clinical blood test, determination of glycemic levels, 

fasting insulin, urea, electrolytes, coagulogram; 

• analysis of biochemical indicators of liver condition - 

aspartate aminotransferase (AST), alanine 

aminotransferase (ALAT), ALT/AST ratio, γ-glutamyl 

transpeptidase (GGTP), total bilirubin and its fractions; 

• lipid profile - cholesterol, triglycerides, high-density 

lipoproteins (HDL), low-density lipoproteins (LDL); 

• oral glucose tolerance test, glycated hemoglobin 

(HbA1c); 

• determination of the HOMA-IR and ISI-gly indices as 

indicators of insulin resistance;  

• assessment of the functional state of the thyroid 

gland; 

• exclusion of Wilson's disease - concentration of 

ceruloplasmin, copper in the blood serum, urinary 

copper excretion per day; 

• exclusion of cystic fibrosis - sweat test; 

• exclusion of celiac disease - antibodies (IgA) to tissue 

transglutaminase, total IgA; 

• other tests in accordance with the medical history - 

exclusion of viral hepatitis, autoimmune liver diseases 

(liver autoantibodies), serum immunoglobulins. 

The currently recommended test for screening for 

steatohepatitis is the determination of ALT activity [1, 

18]. NASH is more often found in children with ALT ≥ 80 

U/L compared with children with enzyme activity < 80 

U/L (41% and 21%, respectively). If the ALT level is > 80 

U/L for ≥ 3 months, clinical data should be assessed, 

since such an increase in enzyme activity may indicate 

existing hepatocyte damage  [18]. In the absence of 

risk factors for the development of NAFLD (excessive 

weight gain, type 2 diabetes mellitus, obstructive sleep 

apnea), ALT activity is recommended to be tested 

every 2-3 years [1]. In the presence of these risk factors, 

it is recommended to repeat the ALT test in blood 

serum [1], the frequency of repeat testing is not 

defined in international recommendations, the issue is 

resolved individually. A number of studies have shown 

that overexpression of HIF-2a (hypoxia-inducible 

factor) [19], visfatin [20, 21], increased concentrations 

of C-reactive protein, apolipoprotein A1, haptoglobin 

and α2-macroglobulin [22], fibroblast growth factor 21 

[23], adiponectin and adiponectin receptor 2 [24] are 

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VOLUME 04 ISSUE 03 PAGES: 24-35 

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associated with the progression of NAFLD, 

suppression of fatty acid β-oxidation and induction of 

lipogenesis in the liver  [19]. In addition, the above 

factors have pronounced lipotoxicity and trigger a 

cycle of progressive damage to hepatocyte organelles, 

leading to their apoptosis and aseptic inflammation 

[25]. Inflammation of adipose tissue and intestinal 

dysbiosis provide substrates for the formation of 

reactive oxygen species that enhance inflammation 

[25]. And finally, progression from simple steatosis to 

NASH provides an imbalance between pro-

inflammatory (TNFα-, resistin, IL-6) and anti-

inflammatory (adiponectin) cytokines with the 

dominant effects of the former [26]. 

Histological examination 

Liver biopsy is a test for the diagnosis and differential 

diagnosis of steatosis and steatohepatitis and 

exclusion of other diseases, recommended by 

ESPGHAN and called the reference test in consensus 

[4]. Histological signs of NASH are the presence of 

hepatocytes with fatty macrovesicles and a nucleus 

displaced towards the membrane, changes in 

hepatocytes like balloon degeneration, mixed 

inflammation in the liver lobules [4]. Also, when 

studying liver biopsies, perisinusoidal-pericellular 

fibrosis along with megamitochondria, acidophilic 

bodies and glycogenated nuclei may be noted, but are 

not required for the morphological diagnosis of NASH. 

Liver biopsy cannot be widely used due to its 

invasiveness and the risk of complications in both 

adults and children. There are no specific 

recommendations for selecting children for this study 

in international guidelines; in fact, it is indicated for all 

patients with NASH. The high cost (according to our 

estimates, in Russia - 12,000-20,000 rubles) of this 

diagnostic method is also a problem [1]. 

Instrumental visualization 

In the instrumental diagnosis of NAFLD, ESPGHAN 

(2012) recommends the use of ultrasonography, 

computed tomography, magnetic resonance imaging, 

and liver fibroscanning [4], which are also appropriate 

for NASH, primarily to identify fibrosis of the liver tissue 

that occurs along with inflammation. 

Ultrasound diagnostics (ultrasound) is a method of 

qualitative assessment of the condition of liver tissue, 

available in most medical institutions. The sensitivity of 

ultrasound for detecting liver changes in NAFLD is 60-

96%, specificity is 84-100% [4]. There is no doubt that 

the results of ultrasound diagnostics depend on the 

apparatus and the skills of the doctor performing the 

examination. However, this method is fast enough to 

diagnose liver damage - the duration of the study is 

about 20 minutes.  The threshold for detecting changes 

in the liver parenchyma by ultrasound in patients with 

NAFLD is the presence of fatty infiltration of ≥ 20% of 

hepatocytes [4]. To assess the degree of NAFLD, an 

ultrasound fatty liver index has been proposed - a new 

scoring system in the range of 2-8 points, based on 

such indicators as the intensity of ultrasound signals of 

the liver relative to the kidneys, weakening of the 

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ultrasound signal in the retroperitoneal space, unclear 

visualization of blood vessels, difficulty in visualization 

gallbladder walls, diaphragm, detection of focal 

changes in the liver [27]. In a study by H.K. Liu et al. An 

ultrasound fatty liver index score ≥ 6 was a predictor of 

steatohepatitis in children with NAFLD, and the 

authors proposed using this score to predict 

steatohepatitis in children with NAFLD without 

requiring liver biopsy [28]. 

Computed tomography (CT) allows one to assess the 

presence and degree of fatty infiltration of the liver, i.e. 

conduct a qualitative and quantitative analysis of the 

condition of the liver tissue. The sensitivity of CT for 

detecting liver changes in NAFLD is 82%, specificity is 

100% [4]. Moreover, CT makes it possible to identify 

steatosis with fatty infiltration of more than 30% of 

hepatocytes [4]. CT scanning is available and 

performed quite quickly - it takes no more than 5 

minutes to obtain the result. However, it should be 

emphasized that this method is associated with 

ionizing radiation, which limits its use in children. 

Magnetic resonance imaging (MRI) also allows 

qualitative and quantitative assessment of fatty 

infiltration of the liver. The method is widely available, 

but still relatively expensive [4]. Liver density 

assessment occurs in T1 mode. The sensitivity of the 

method for detecting liver changes in NAFLD is 100%, 

specificity is 90.4% [4]. An MRI requires 10-15 minutes. 

However, MRI has a number of contraindications: the 

presence of metal elements in the patient’s body, as 

well as excess body weight, for which the positioning 

table is not designed. It should be noted that 

assessment using MRI is possible with fatty infiltration 

of the liver of the 1st degree - 5-30% of hepatocytes [4]. 

1H-MR spectroscopy - magnetic resonance 

spectroscopy - a method that allows you to 

qualitatively and quantitatively assess the condition of 

the liver parenchyma. The method is highly expensive 

(from 5,000 to 15,000 rubles). The study is carried out 

in T2 mode - fat-saturated spectroscopy, measuring the 

area at the peak of lipid resonance. The sensitivity of 

the method is 87-100%, diagnostic accuracy is 80-85% 

[4]. 

Liver elastography allows you to evaluate fatty 

infiltration of the liver and detect fibrous changes. The 

method is based on measuring the density of liver 

tissue through shear wave propagation. The sensitivity 

of the method for cases of NAFLD is 81-85%, specificity 

is 74-78% [4]. The duration of liver elastography is no 

more than 20 minutes. The test is non-invasive, fast, 

reproducible [15]. Despite its advantages, this method 

is not widely used in medical institutions due to a 

shortage of appropriate equipment and is not included 

in Russian standards for examining children. Y.D. Kwon 

et al., examining children with obesity (including NAS 

and NASH) found fibrosis (liver stiffness > 5.5 kPa) in 30 

(51%) of 59 children, while in the group of children 

without obesity there were cases of fibrosis were not 

found. The liver stiffness indicator correlated with the 

activity of AST (r = 0.525), ALT (r = 0.594), insulin 

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VOLUME 04 ISSUE 03 PAGES: 24-35 

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resistance (HOMA-IR, r = 0.400) and the AST-to-

platelet ratio index (r = 0.480) [29]. 

Calculation indices 

Currently, to assess the presence and histological 

activity of fibrosis, inflammation, steatosis and other 

processes in NAFLD and NASH, calculated indices are 

used that take into account the values of biochemical 

parameters and minimal anamnestic data. These 

indices have demonstrated their information content 

and ease of use, but their disadvantage is their high 

cost (11,000-20,000 rubles). We also note that it was 

not possible to find information on the diagnostic 

accuracy of these tests (sensitivity, specificity). The 

NAS scale (NAFLD activity score, NAFLD activity scale) 

is proposed for semi-quantitative assessment of 

steatosis (in %), lobular inflammation, balloon 

degeneration, and the stage of fibrosis. Thus, the 

severity and stage of NAFLD is characterized [4, 30]. 

For each item on the scale there is a score from 0 to 2 

points. A total score of ≥ 5 points allows a diagnosis of 

NASH [4, 31]. 

The FibroMax test takes into account the values of 10 

biochemical blood test indicators: ALT, AST, GGTP, 

total bilirubin, α2-macroglobulin, apolipoprotein A1, 

haptoglobin, total cholesterol, triglycerides, glucose. 

Mathematical algorithms (5 in total) based on the 

values of these indicators determine such 

characteristics of the liver condition as:  

severity of fibrosis with staging (F0-F4) in accordance 

with the international METAVIR system (FibroTest); 

• activity of necrotic and inflammatory processes with 

determination of degree (A0-A3) - also in accordance 

with the METAVIR system (ActiTest); 

• presence and severity of liver steatosis (SteatoTest); 

• presence of alcoholic steatohepatitis in alcohol 

abusers (EshTest); 

• the presence of NASH in patients with excess body 

weight, insulin resistance, hyperlipidemia, as well as in 

patients with diabetes mellitus (Nash-Test, from the 

English NASH - non-alcoholic steatohepatitis)  [31]. 

A shortened version of the FibroMax test called 

FibroTest is also carried out, when only 2 calculation 

algorithms are used based on the results of 

mathematical processing of 6 biochemical blood 

parameters: α2-macroglobulin, haptoglobin, 

apolipoprotein A1, GGTP, total bilirubin, ALT. In this 

case, the assessment is given only on two scales - the 

severity of liver fibrosis and the activity of the 

necroinflammatory process in the liver. 

Therapy  

Lifestyle change 

Currently, the main treatments for children with NASH, 

as with other forms of NAFLD, are a low-calorie diet 

and physical activity aimed at correcting overweight or 

obesity. Lifestyle modification with dietary changes 

and increased physical activity is recommended as first-

line therapy for all children with NAFLD/NASH [1]. 

Limiting the consumption of sugary drinks is also 

indicated [1]. In accordance with NASPGHAN 

recommendations, it is necessary to increase children's 

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VOLUME 04 ISSUE 03 PAGES: 24-35 

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physical activity to moderate or vigorous intensity and 

limit time spent on gadgets to 2 hours per day.  [1]. The 

Russian Association of Endocrinologists advises 

following similar recommendations when treating 

obese children [3]. Special Russian recommendations 

for the treatment of children with NAFLD and NASH 

have not been developed. 

Drug treatment 

It is important to emphasize from the outset that 

NASPGHAN (2017) [1] does not recommend the use of 

any medications or dietary supplements for the 

treatment of patients with NAFLD/NASH. In 

experimental studies on mice with NAFLD, it was 

shown that metformin relieves hepatomegaly, 

steatosis and abnormal aminotransferase activity [32], 

which was confirmed by the results of some clinical 

studies [33]. However, subsequent more rigorous 

clinical studies did not reveal a reduction in histological 

changes in the liver in patients with NAFLD during 

metformin therapy. [34]. 

According to the results of a randomized, double-blind, 

placebo-controlled study, treatment with high doses 

(28-35 mg/kg per day) of ursodeoxycholic acid (UDCA) 

for 12 months reduces aminotransferase activity and 

the concentration of serum markers of fibrosis in adult 

patients with histologically confirmed NASH [35]. A 

Russian observational study noted that after 

treatment with UDCA at a dose of 12-15 mg/kg, 

normalization of liver enzyme activity was achieved in 

96% of children with NASH [36]. A randomized 

controlled trial found that treatment with UDCA and 

vitamin E for 2 years reduced the activity of AST and 

ALT and the severity of hepatic steatosis in patients 

with NASH [37]. In experimental studies on animal 

models, in addition, it was shown that UDCA drugs 

have, among other things, antifibrotic and 

antiapoptotic effects [38]. According to the 

instructions for the use of UDCA drugs approved by the 

Russian Ministry of Health, they are indicated, incl. and 

patients with NASH and do not have any 

contraindications for children, which means they can 

be used in children at a dose of 10-15 mg/kg per day for 

6-12 months or more. However, the effectiveness and 

safety of UDCA in children with NAFLD/NASH have not 

yet been studied in high-quality clinical studies. 

In the official instructions of the State Register of 

Medicines of the Russian Federation, some 

preparations of essential phospholipids or their 

combination with other components of 

hepatoprotective action indicate fatty degeneration 

and liver degeneration, and contraindications include 

children under 3 or up to 12 years of age. Therefore, 

their use in the treatment of NASH in children of the 

appropriate age is possible. However, it should be 

noted that high-quality controlled studies of the 

effectiveness and safety of essential phospholipids for 

steatohepatitis and liver steatosis in children have not 

been conducted. There is data on the use of various 

nutritional supplements in the treatment of patients 

with steatosis and steatohepatitis. A randomized study 

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in children showed the effectiveness of a combination 

of ascorbic acid + vitamin E / ω3-polyunsaturated fatty 

acids [39], in randomized double-blind placebo-

controlled studies in adults - δ-tocotrienol [40], in 

children - the probiotic Lactobacillus rhamnosus GG 

[41] , synbiotics [42]. The effectiveness of Lactobacillus 

rhamnosus GG was also confirmed in a Russian 

observational study involving children [43]. The use of 

ω3-polyunsaturated fatty acids in children also led to 

relief of the manifestations of NASH, which is 

described in detail in a literature review by S. Spahis et 

al. [44]. The use of these dietary supplements reduced 

ALT activity, body mass index and/or the number of 

hepatocytes involved in fatty infiltration to varying 

degrees. 

CONCLUSION 

NASH, like other forms of NAFLD, is a common 

pathology of childhood, which is associated with a 

steady increase in the number of children with 

overweight and obesity in the population. 

Unfortunately, due to current dietary trends and a 

sedentary lifestyle, a decrease in the incidence of 

NAFLD cannot be expected in the near future. The 

exact causes and pathogenetic mechanisms of 

progression of steatohepatosis to steatohepatitis are 

not completely clear. However, there is no doubt that 

recurrent or persistent necrotic and inflammatory 

changes in the liver will eventually lead to fibrosis. 

Detection of liver damage in children with overweight 

or obesity should become an additional motivating 

factor for parents, the child himself, pediatricians and 

other specialists to intensify efforts to change the 

patient’s lifestyle. This is the main and effective 

method of treating NASH and NAFLD in general, and 

the administration of hepatoprotectors and 

antioxidants in long courses serves as an addition that 

can slow down the progression of the pathological 

process in the liver. 

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