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Clinical, laboratory and molecular-genetic markers of the
progression of non-alcoholic fatty liver disease (literature
review and own data)
Хamrayev A.A
1
Yuldasheva D.H.
2
Bukhara state medical institute
ARTICLE INFO
ABSTRACT
Article history:
Received January 2021
Received in revised form
15 January 2021
Accepted 20 February 2021
Available online
7 March 2021
Non-alcoholic fatty liver disease (NAFLD) is one of the most
common diseases in hepatology. First of all, this is associated
with a high risk of progression of NAFLD with the development
of non-alcoholic steatohepatitis (NASH), liver failure, and
hepatocellular carcinoma. Epidemiological and genetic studies
have shown the relationship between the morphological stage of
NAFLD and hereditary factors. The article provides a review of
the literature on the cytokines, MBOAT7 and GCKR genes. Also, a
variant of the MBOAT7 and GCKR gene is associated with a high
risk of fibrosis in patients with NAFLD and elevated serum
triglyceride levels.
2181-1415/© 2021 in Science LLC.
This is an open access article under the Attribution 4.0 International
(CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/deed.ru)
Keywords:
Non-alcoholic fatty liver
disease
Nonalcoholic steatohepatitis
Cytokines
MBOAT7 gene
GCKR gene
Cirrhosis
Lipids
Obesity
Alkogolsiz yog'li jigar kasalliklarini rivojlanishining klinik,
laboratoriya va molekulyar-genetik markerlari (adabiyotlarni
ko'rib chiqish va o'z ma'lumotlari)
АННОТАЦИЯ
Калит сўзлар:
Alkogolsiz yog'li jigar
kasalligi
Alkogolsiz steatohepatit
Sitokinlar
MBOAT7 geni
Alkogolsiz jigar yog'li kasalligi (NAFLD) gepatologiyada eng
keng tarqalgan kasalliklardan biridir. Avvalo, bu alkogolsiz
steatohepatit (NASH), jigar etishmovchiligi va gepatosellular
karsinomaning rivojlanishi bilan NAFLD rivojlanishining yuqori
xavfi bilan bog'liq. Epidemiologik va genetik tadqiqotlar
1
Tashkent medical Academy. Bukhara state medical institute, Bukhara, Uzbekistan
2
Tashkent medical Academy. Bukhara state medical institute, Bukhara, Uzbekistan
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400
GCKR geni
Siroz
Lipidlar
Semirish
NAFLDning morfologik bosqichi va irsiy omillar o'rtasidagi
bog'liqlikni ko'rsatdi. Maqolada sitokinlar, MBOAT7 va GCKR
genlari haqidagi adabiyotlar ko'rib chiqilgan. Shuningdek,
MBOAT7 va GCKR genlarining bir varianti NAFLD va yuqori qon
zardobida triglitseridlar darajasi yuqori bo'lgan bemorlarda
fibroziya xavfi yuqori.
Клинические, лабораторные и молекулярно-генетические
маркеры прогрессии неалкогольной жировой болезни
печени (обзор литературы и собственные данные)
АННОТАЦИЯ
Ключевые слова:
Неалкогольная жировая
болезнь печени
Неалкогольный
стеатогепатит
Цитокины
Ген MBOAT7
Ген GCKR
Цирроз
Липиды
Ожирение
Неалкогольная жировая болезнь печени (НАЖБП) - одно
из самых распространенных заболеваний в гепатологии.
Прежде
всего,
это
связано
с
высоким
риском
прогрессирования НАЖБП с развитием неалкогольного
стеатогепатита (НАСГ), печеночной недостаточности и
гепатоцеллюлярной карциномы. Эпидемиологические и
генетические исследования показали взаимосвязь между
морфологической стадией НАЖБП и наследственными
факторами. В статье представлен обзор литературы по
цитокинам, генам MBOAT7 и GCKR. Кроме того, вариант гена
MBOAT7 и GCKR связан с высоким риском фиброза у
пациентов с НАЖБП и повышенными уровнями
триглицеридов в сыворотке.
THE URGENCY OF THE PROBLEM
Today, non-alcoholic fatty liver disease (NAFLD) attracts the attention of a wide range
of specialists both in our country and abroad. Currently, non-alcoholic fatty liver disease
(NAFLD) is one of the most common diseases in hepatology, leading to a deterioration in the
quality of life, disability and death. The overall prevalence of NAFLD in the population ranges
from 10 to 40% [3,5,9,19,38].
Non-alcoholic fatty liver disease is not related to alcohol consumption, a chronic
disease characterized by the accumulation of fat in liver cell and that plays an important role
in diseases of the gastrointestinal tract [3,11].
Thus type of NAFLD may be, as independent disease, combined with obesity, 2
nd
type
of diabetes mellitus and dyslipidemia, and according to a several authors, secondary
functional violations of liver, for instance, with dyslipidemia, they can manifest as a NAFLD. In
the early stages of the NAFLD are characterized by ineffectiveness of specific treatment and
progressive progression of the disease due to the nonspecific clinical signs [3,25,27].
NAFLD - progressive, chronic multifactorial steatosis of liver – (accumulation of fat in
the liver, fatty dystrophy of hepatocytes), steatohepatitis – formation of inflammatory
infiltrate around the site of necrosis in hepatocytes, non-alcoholic fibrosis-cirrhosis:
destruction of liver architectonics and the disease complicated by connective tissue growth,
that has been the main focus of local and foreign hepatologists for the last 10 years [3,15,34].
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When the disease is periodic in 12-40% patients after 8-13 years may convert to non-alcohol
steatohepatitis, from that in 15% patients may be liver cirrhosis and liver failure. After 10
years liver cirrhosis may convert to hepatocellular carcinoma in 7 % patients. NAFLD - the
facts in last 10 years confirm growth of disease [26,35,37]. NAFLD is widespread in western
Europe and USA. The spreading in common population of NAFLD L is not learnt well, but some
authors determined that occurs 3-58% in Italy and USA [9,35].
The growth rate of NAFLD is problem and that will evaluate with propensity to obesity.
As the level of obesity increases, the severity of the disease also increases [3,7,15,17,29].
NAFLD 3-100 % occurs with obesity. In that situation when patients are checked at ultrasound
examination, fatty dystrophy of liver will found [7,30]. The scientific researches show that,
NAFLD occurs 70% with 2
nd
type diabetes mellitus [2,24,30]. Thus, the progressive
progression and prevalence of the disease is one of the current problems of clinical medicine
due to the observation of the time when the working capacity of the population is preserved,
close clinical signs are observed in the late stages of the disease [38,39].
There are many causes of development of the fatty steatosis of liver. Primary steatosis
mostly, appears on the basis of obesity, hyperlipidemia, 2
nd
type diabetes mellitus [4,10,15].
The cause of developing secondary fatty hepatosis is consumption drugs of some groups
(steroid hormones, substitution hormonal therapy, antiarrhythmic and antibacterial drugs,
cytostatic, non-steroidal anti-inflammatory drugs), chronic inflammatory diseases of the
gastrointestinal tract, sudden weight loss, parenteral nutrition, gestational age hypoxia,
Wilson Konovalov disease, lipoproteinemia, familial liver steatosis, glycogen accumulation
disease [10,12,13]. Based on the entry of free fatty acids (FFA) into the liver, triglycerides
accumulate in the liver the beta oxidation rate of FFA in the liver mitochondria decreases, and
the synthesis of fatty acids increases. As a result, the synthesis of very low-density lipoproteins
is reduced, triglycerides are excreted from the liver [12,13].
In developing of steatosis “First impact” is – gathering of FFA in hepatocytes, decreasing
of oxidation and inhibition of triglyceride elimination. Different level of inflammation and
fibrinogenase are observed in response to oxidative stress molecules (aldehydes). Oxidative
stress products induce the expression of matrix – linked genes. Oxidative stress associated
with the immune response, fibrinogenase develops in the trigger. Stress of hepatocytes with
lipids and FFA leads to the development of functional insufficiency in the mitochondria and
the formation of steatosis occurs. Progressive progression of steatosis makes condition for
developing steatohepatitis. Additional oxidative stress, peroxidase oxidized lipids disturb the
cellular defense mechanism and inflammation and necrosis occur. NAFLD stimulates
formation of free radicals from endogenous ketones, food nitrosamines, aldehydes,
cytochrome Р450 (CYP) 2Е1. 18 CYP 2Е1 ketone and fatty acids can be cytochrome mediators
[10].
The inflammatory process may develop endotoxinemia in intestinal dysbacteriosis.
Lipopolysaccharide, a gram-negative bacterium that enters the portal vein, activates Toll-like
receptors in response to type 4 immunity and develops inflammation and fibrosis (30,33). In
NAFLD, endotoxemia pro-inflammative cytokines (TNF), Interleukin-6,8 and this increase the
expression of cytokine receptors [27,34]. Serum concentrations are elevated in obese
individuals TNF-α. TNF-α activates a protein that stimulates protective inflammatory
reactions - inhibitor of kappa kinase beta (IKKβ) in adipocytes and hepatocytes, which leads
to impaired binding insulin receptor. Smooth muscle and endothelial cells of the vessel wall
under the influence of TNF-α enhance the production of monocytic chemotactic protein-1
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(MCP-1), which plays a leading role in the pathogenesis of atherosclerosis. It is noteworthy
that cytokines are one of the main stimulants of liver regeneration. It is known that TNF-α is
able to initiate liver necrosis, but necrosis does not occur in normal hepatocytes, because TNF-
α-celeft genes are usually expressed at minimal level [8,14]. Serum TNF-α levels are not the
same in patients patients with hepatic steatosis and NASH and, as a rule, higher in patients
with NASH, although the difference is not always statistically significant [2,8,14]. Interleukin-
6 (IL-6) has a special role as a “hepatocyte-activating factor”. IL-6 can induce the synthesis of
many acute phase proteins, such as fibrinogen and C-reactive protein (CRP), an increase in
which is common a known risk factor for CVD. It has been proven that cytokines are important
mediators of steatohepatitis [14]. In this process the primary role is played by the tumor
necrosis factor holi alpha (TNF-a) and interleukin 6 (IL-6). TNF-a stimulates the synthesis of
fatty acids in the liver, increases the level of serum triglycerides [8,13,14] and stimulates the
production of VLDL by the liver [12]. TNF-a can cause both the death of hepatocytes and their
proliferation, and is critically involved in the pathogenesis of liver fibrosis in NASH [2,8,14].
Last studies have shown that adipose tissue, namely, visceral fats, alters endocrine
content, produces adipokine-hormones, which affect lipid metabolism, as well as the function
of other organs and systems [5,18,36]. Changes in the amount of adipokines increase tissue
infiltration monocytes and macrophages, pro-inflammation induct cytokines. Prolonged
steatosis and local inflammation can lead to fibrosis and then may convert cancer. NAFLD over
time increases the risk of cirrhosis, hepatocellular cancer, which results in liver resection and
transplantation [6].
In obesity, the release of high concentrations of leptins in the blood stimulates the
secretion of other neuropeptides: melanocytostimulating hormone, propiomelanocortsin,
neuropeptide, corticotropin, corticotroping releasing factor. All of the above peptides cause
dysfunction of the sympathetic nervous system, activate lipolysis in fat storage, accelerate the
entry of FFA into the liver. FFA stimulates glycogenesis in the liver, inhibits insulin secretion,
develops insulin resistance[3,11,16,39].
The development of fatty liver dystrophy occurs through exogenous and endogenous
mechanisms. As a result of intestinal absorption of exogenous fatty acids, glycerin, glucose,
galactose, fructose, the endogenous mechanism - increased peripheral lipolysis, decreased
consumption of fatty acids from liver cells, increased fat synthesis, protein deficiency in liver
cells, decreased liver enzyme activity, very low lipoprotein density increase in excretion by
hepatocytes [3]. Dyslipoproteinemia (DLP) is characterized by a change in homeostatic
constant, a violation of the functioning of systems. DLP can damage the liver as a target organ
and cause atherosclerosis in the arteries parallel to it. A group of researchers have noted that
dyslipidemia is a disorder of the process of bile formation and secretion as a result of damage
to the hepatocyte membrane. Other authors have suggested that DLP in hepatic steatosis is a
“safe condition” and that the etiologic factor must be ruled out [15,23]. These ideas are
complicated because in hepatic steatosis mitochondria, liver cell lysosomes are damaged, FFA
is not consumed, cholestasis and hyperlipidemia may develop.
In NAFLD liver cell function is impaired, large amounts of cholesterol and small
amounts of phospholipids and bile acids accumulate in the bile ducts, bile has lithogenic
properties, and gallstone disease develops [15,23], resulting in impaired secondary
metabolism [3]. NAFLD is 5 times more common in patients than in gallstone disease in the
population. Gallstones were observed in 18.2% and 31.1% of patients with nonalcoholic
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steatosis and steatohepatitis. At the same time, cirrhosis of the liver and cholelithiasis were
observed in 41.7% of patients [19].
Hyperinsulinemia is the main link in the development of IR-HI-obesity-IR. Today, an
increase in fat tissue reserves based on a high-calorie diet increases the stress on insulin. Lack
of physical activity leads to insulin resistance in adipose tissue, hyperinsulinemia is formed as
a result of decreased tissue sensitivity to insulin.
The most common risk factors are a diet with an excess of calories, saturated fat, easily
digestible carbohydrates and fructose, and low physical activity. In some cases, (especially
among children and adolescents), a hereditary predisposition to NAFLD can be confirmed,
arising from defects in the genetic material (PNPLA3 and TM6SF2 gene, MBOAT7 gene, GCKR
gene) [2,8,13,14,17,32,34]. Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver
damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD.
The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic
risk factors for nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver disease
(NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-
cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive
NAFLD, but the impact on hepatic carcinogenesis is unknown [1,8,13,14,22].
The GCKR gene encodes a protein involved in the regulation distribution of glucokinase
between the cytosol and the nucleus in hepatocytes and, thus, in the process of utilization lysis
of glucose by liver cells [1,32]. Option p.P446L (rs1260326) of the GCKR gene, first identified
in 2011, inhibits glucokinase indirectly through an increase in the level of fructose-6-
phosphate [1,20]. This leads to increased absorption of glucose by cells, liver and, in turn,
helps to increase activity of de novo lipogenesis processes and a simultaneous decrease in
serum glucose and insulin levels [1,13,14]. The combination of minor alleles I148M and P446L
of the PNPLA3 and GCKR genes is associated with steatosis up to 30% in the liver acinus (the
severity of steatosis according to histological examination) in obese children [1,13]. Also, the
p. P446L variant of the GCKR gene is associated with a high risk of developing fibrosis in
patients with NAFLD and elevated serum triglyceride levels [1,20]. The variant rs641738 was
recently identified gene MBOAT7 encoding lipophosphatidylinositol acyltransferase. This
genetic variant is not only increases the risk of developing cirrhosis of the liver in individuals
with consuming alcohol, but also, as was shown later, increases the risk of developing non-
alcoholic steatohepatitis and liver fibrosis in patients with NAFLD [1,24,29]. The MBOAT7
gene encodes lipophosphatidylinositol acyltransferase, which catalyzes the remodeling of the
acyl chain of phosphatidylinositols, binds arachidonic acid to lysophosphatidylinositol and
reduces the level of free arachidonic acid in neutrophils [1,21]. Arachidonic acid, in turn red,
induces apoptosis of hepatocytes, causing reproduction palpation and fibrosis of liver tissue
[1]. Probably for this reason, the rs641738 variant of the MBOAT7 gene, which leads to a
decrease in MBOAT7 expression, is associated with a lower risk of steatosis than PNPLA3 p.
I148M or TM6SF2 p. E1267K, but with an increase in the activity of inflammation in the liver
and the development of fibrosis in NAFLD [28].
NAFLD is asymptomatic in most patients (48-100%). The remaining patients have
abdominal discomfort and blunt pain under the right rib. Patients with cardiovascular
pathology, digestive, endocrine and tumor diseases, as well as other diseases of the liver are
often diagnosed suddenly at the time of complaint [3,7,29,31,33].
There will be no changes in blood biochemical analysis. Sometimes urobilinogenuria,
hypertriglyceremia can be detected. ALT activity can significantly exceed the norm by 1.5-2
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times. Obesity, 2nd type DM, hyperlipidemia, thymol test, increased levels of alpha 2 and
gamma globulin are seen [2,14].
An anamnesis of alcohol is denied at NAFLD. Transferin, often sialic acid and
mitochondrial isoenzyme AST is sensitive and specific, but is rarely used [2,16,19]. Because a
perfectly collected anamnesis is an important diagnostic method in general practitioners.
CONCLUSION.
Like fatty hepatosis, non-alcoholic steatohepatitis is an independent disease that
should be kept in mind when conducting differential diagnostics in patients with a stable
increase in serum ALT and AST, especially in the presence of obesity, diabetes, and
hyperlipidemia. Epidemiological and genetic studies have shown the relationship between the
morphological stage of NAFLD and hereditary factors. The data obtained confirm the
importance of the discussed cytokines in the evolution of hepatic steatosis into
steatohepatitis, and also indicate the possibility of using their indicators as non-invasive
markers of steatosis and the activity of inflammation in the liver in patients with NAFLD.
Genetic factors increase risk for progressive NAFLD.
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