Non-alcoholic fatty liver disease: clinical guidelines

List of Abbreviations

AH – arterial hypertension

ALT – alanine aminotransferase

AMPK – AMP-activated protein kinase

ATP – adenosine triphosphate

AMP – adenosine monophosphate

ASCVD – atherosclerotic cardiovascular disease

AST – aspartate aminotransferase

ARB II – angiotensin II receptor blockers

ULN – upper limit of normal

WHO – World Health Organization

GGT – gamma-glutamyl transferase

HMG-CoA reductase – 3-hydroxy-3-methylglutaryl-coenzyme A reductase

GLP-1 – glucagon-like peptide-1

HCC – hepatocellular carcinoma

CI – confidence interval

DPP-4 – dipeptidyl peptidase-4

GD – gallstone disease

HSCs – hepatic stellate cells

ACE inhibitor – angiotensin-converting enzyme inhibitor

CHD – coronary heart disease

IL – interleukin

SGLT2i – sodium-glucose cotransporter 2 inhibitors

BMI – body mass index

IR – insulin resistance

IFN – interferon

CP – clinical guidelines

HDL – high-density lipoproteins

LDL – low-density lipoproteins

HCF – healthcare facility

MASLD – metabolic dysfunction-associated steatotic liver disease

MASH – metabolic dysfunction-associated steatohepatitis

MetALD – metabolic dysfunction-associated steatotic liver disease with increased alcohol intake

MetS – metabolic syndrome

ICD – International Classification of Diseases

MRI – magnetic resonance imaging

MRI-PDFF (Magnetic Resonance Imaging-Derived Proton Density Fat Fraction) – magnetic resonance imaging with proton density fat fraction estimation

NAFLD – non-alcoholic fatty liver disease

NASH – non-alcoholic steatohepatitis

OGTT – oral glucose tolerance test

LPO – lipid peroxidation

PUFA – polyunsaturated fatty acids

RAAS – renin-angiotensin-aldosterone system

RCT – randomized controlled trial

eGFR – estimated glomerular filtration rate

DM – diabetes mellitus

FFA – free fatty acids

CVD – cardiovascular disease

TG – triglycerides

UDCA** – ursodeoxycholic acid**

US – ultrasound examination

TNF-α – tumor necrosis factor-alpha

CKD – chronic kidney disease

Chol – cholesterol

CHF – chronic heart failure

LC – liver cirrhosis

ALP – alkaline phosphatase

EGD – esophagogastroduodenoscopy

EPL – essential phospholipids (phospholipids)

APRI (Aspartate Aminotransferase to Platelet Ratio Index) – aspartate aminotransferase to platelet ratio index

AUROC (Area Under Receiver Operating Characteristic Curve) – area under the receiver operating characteristic curve

Bax (BCL2 Associated X Protein) – bcl-2-associated X protein

Bcl-2 (B-Cell Leukemia/Lymphoma 2) – intracellular protein factor, regulator of apoptosis

BSEP (Bile Salt Export Pump) – bile salt export pump

cAMP/PKA (cAMP-Dependent Protein Kinase) – cyclic AMP-dependent protein kinase A

CAP (Controlled Attenuation Parameter) – controlled attenuation parameter

CCL2 (C-C Motif Chemokine Ligand 2) – C-C motif chemokine ligand 2

ChREBP (Carbohydrate-Responsive Element-Binding Protein) – carbohydrate-responsive element-binding protein

DGUOK (Deoxyguanosine Kinase) – mitochondrial deoxyguanosine kinase

FIB-4 (Fibrosis-4 Index) – fibrosis-4 index

FLI (Fatty Liver Index) – fatty liver index

FXR (Farnesoid X Receptor) – farnesoid X receptor

GPBAR1 (The G Protein-Coupled Bile Acid Receptor 1) – G protein-coupled bile acid receptor 1

Hb_A1c – glycated hemoglobin (A1c)

HOMA-IR (Homeostasis Model Assessment for Insulin Resistance) – homeostasis model assessment for insulin resistance

JNK – c-Jun N-terminal kinase, stress-activated protein kinases

LOLA – L-ornithine L-aspartate (ornithine)

M2 – type 2 macrophages (alternatively activated macrophages)

MPV17 (Mitochondrial Inner Membrane Protein MPV17) – mitochondrial inner membrane protein MPV17

mTOR (Mechanistic Target of Rapamycin) – mechanistic target of rapamycin

NAFLD (Non-Alcoholic Fatty Liver Disease) – non-alcoholic fatty liver disease

NAS (NAFLD Activity Score) – NAFLD activity score

NFS (NAFLD Fibrosis Score) – NAFLD fibrosis score

NF-κB (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) – nuclear factor kappa-light-chain-enhancer of activated B cells

NHE3 (Sodium-Hydrogen Exchanger 3) – sodium-hydrogen exchanger 3

NLR (NOD-Like Receptor) – NOD-like receptors

NPC1L1 (Niemann-Pick C1-Like 1) – Niemann-Pick C1-like 1 protein (sterol transporter)

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) – proprotein convertase subtilisin/kexin type 9

PDFF (Proton Density Fat Fraction) – proton density fat fraction

PNPLA3 (Patatin-Like Phospholipase Domain-Containing Protein 3) – patatin-like phospholipase domain-containing protein 3, adiponutrin gene

POLG (DNA Polymerase Subunit Gamma) – DNA polymerase subunit gamma

PPAR (Peroxisome Proliferator-Activated Receptor) – peroxisome proliferator-activated receptors

PRRs (Pattern Recognition Receptors) – pattern recognition receptors

SREBP-1c (Sterol Regulatory Element-Binding Transcription Factor 1c) – sterol regulatory element-binding transcription factor 1c

SREBP-2 (Sterol Regulatory Element-Binding Transcription Factor 2) – sterol regulatory element-binding transcription factor 2

TGF-β (Transforming Growth Factor Beta) – transforming growth factor beta

TGR5 (Takeda G Protein-Coupled Receptor 5) – Takeda G protein-coupled receptor 5

Th (T-Helper) – T-helper cell

THR-β (Thyroid Hormone Receptor β) – thyroid hormone receptor beta

TLR (Toll-Like Receptors) – toll-like receptors

TM6SF2 (Transmembrane 6 Superfamily Member 2) – transmembrane 6 superfamily member 2

VDR (Vitamin D-Receptor) – vitamin D receptor

Terms and Definitions

Arterial hypertension (AH) is a syndrome of elevated clinical blood pressure (BP) in hypertension and symptomatic AH above threshold values determined as a result of epidemiological and randomized controlled trials (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg), which demonstrated a connection with an increase in cardiovascular risk and the appropriateness and benefit of treatment aimed at reducing BP below these BP levels.

Dyslipidemia refers to conditions where blood lipid and lipoprotein concentrations fall outside the reference ranges.

Fatty liver disease is an umbrella concept that unites liver diseases occurring with steatosis and steatohepatitis.

Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence (clinical trial results) in combination with individual clinical expertise and taking into account patient values and preferences in the process of making decisions about the health status and treatment of the patient.

Disease — a condition arising in connection with the action of pathogenic factors, representing a disruption of the organism's activity, working capacity, and ability to adapt to changing conditions of the external and internal environment, accompanied by changes in the protective-compensatory and protective-adaptive reactions and mechanisms of the organism.

Outcome is any possible result arising from the exposure to a causal factor, prophylactic or therapeutic intervention, all established changes in health status occurring as a consequence of the intervention.

Fatty liver disease of specific etiology is an umbrella concept that includes monogenic diseases, specific phenotypes of drug-induced liver injury, and other diseases in which the development of steatosis/steatohepatitis has a proven cause not associated with metabolic dysfunction and alcohol consumption.

Cardiometabolic risk factors are risk factors for the development of cardiovascular diseases, type 2 diabetes mellitus, and non-alcoholic fatty liver disease.

Conflict of interest is a situation in which a medical or pharmaceutical worker, in the exercise of their professional activities, has a personal interest in obtaining, personally or through a representative of a company, material gain or another advantage that affects or may affect the proper performance of their professional duties due to a contradiction between the personal interest of the medical or pharmaceutical worker and the interests of the patient.

Medicinal products are drugs in the form of dosage forms used for the prevention, diagnosis, treatment of a disease, rehabilitation, preservation, prevention, or termination of pregnancy.

Medical intervention is types of medical examinations and/or medical manipulations performed by a medical worker and another worker entitled to carry out medical activities in relation to a patient, affecting the physical or mental state of a person and having a preventive, diagnostic, therapeutic, rehabilitative, or research focus, as well as artificial termination of pregnancy.

Metabolically associated fatty liver disease combined with excessive alcohol consumption (MetALD) is a chronic liver disease in which non-alcoholic (metabolically associated) fatty liver disease is combined with alcohol consumption averaging 20 to 50 g/day for women and 30 to 60 g/day for men.

Non-alcoholic (metabolically associated) fatty liver disease (NAFLD) is a chronic liver disease associated with metabolic dysfunction, in which macrovesicular steatosis is detected in more than 5% of hepatocytes.

Non-alcoholic steatohepatitis (NASH) is a progressive form (phenotype) of NAFLD, which is characterized by steatosis, intralobular inflammation, ballooning degeneration of hepatocytes, and may occur with the development of pericentral and perisinusoidal (less commonly portal) fibrosis.

Lifestyle modification — measures aimed at the normalization of body weight, diet, and physical activity, the purpose of which is the prevention and treatment of diseases.

Body mass index is an indicator used to diagnose overweight and obesity, as well as to assess its degree (body weight in kilograms divided by height squared in meters, kg/m²).

Clinical trial is any investigation conducted with a human as a subject to identify or confirm clinical and/or pharmacological effects of investigational products and/or to identify adverse reactions to investigational products, and/or to study their absorption, distribution, metabolism, and excretion in order to assess their safety and/or efficacy.

Obesity is a chronic disease characterized by excessive accumulation of adipose tissue in the body, which poses a threat to health and is a major risk factor for a number of other chronic diseases.

Waist circumference is an indicator used to diagnose visceral fat accumulation, abdominal (visceral) obesity.

Patient – an individual to whom medical care is provided or who has applied for medical care, regardless of the presence of a disease and their condition.

Prediabetes is a carbohydrate metabolism disorder in which the criteria for diabetes mellitus are not met, but normal blood glucose values are exceeded (includes any of the disorders: impaired fasting glucose and impaired glucose tolerance).

Working group on the development/updating of clinical guidelines – a team of specialists working together and in a coordinated manner to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

Syndrome – a stable set of several symptoms with a single pathogenesis.

Condition is an alteration of the organism arising from the impact of pathogenic and/or physiological factors that requires medical care.

Type 2 diabetes mellitus is a carbohydrate metabolism disorder caused by predominant insulin resistance and relative insulin deficiency or predominant insulin secretion disorder with or without insulin resistance.

Liver steatosis is the accumulation of fat in the liver, in which lipid accumulation occurs in more than 5% of hepatocytes.

Steatohepatitis is the accumulation of fat in the liver accompanied by intralobular inflammation, ballooning degeneration of hepatocytes, and the possible development of fibrosis.

Level of evidence is the degree of confidence that the obtained effect from the application of a medical intervention is true.

Level of убедительности рекомендаций (Grade of Recommendation) is the degree of certainty in the validity of the intervention effect and that following the recommendations will bring more benefit than harm in a particular situation.

Chronic kidney disease is an umbrella concept that unites all patients with signs of kidney damage and/or decreased function assessed by the glomerular filtration rate, which persist for 3 or more months.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with metabolic dysfunction, in which macrovesicular steatosis is detected in more than 5% of hepatocytes [1, 2]. NAFLD encompasses a pathological spectrum ranging from simple steatosis to steatohepatitis and liver cirrhosis (LC). According to recent concepts, steatosis (simple steatosis) and non-alcoholic steatohepatitis (NASH) represent two separate pathological conditions (phenotypes or forms) with different prognoses [3]:

a) simple steatosis is a condition in which inflammation and fibrosis are absent; at the same time, steatosis is an independent risk factor for the development of cardiovascular diseases (CVD) and their complications [3]. Simple steatosis may have a progressive course with the development of fibrosis, but the rate of its progression is significantly lower than with baseline NASH [4].

b) NASH, which is characterized by steatosis, intralobular inflammation, ballooning degeneration of hepatocytes, and may occur with the development of pericentral and perisinusoidal (less commonly portal) fibrosis. NASH is a clinically progressive form of NAFLD with the risk of developing LC, hepatocellular carcinoma (HCC), as well as CVD and their complications [3].

In 2023, a new nomenclature of fatty liver disease was published [2], which was worked on by a large group of international experts. The very concept of "fatty liver disease" has become a unifying, or umbrella, term, within which various nosological forms are distinguished, including NAFLD. International experts proposed a new name for NAFLD—Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)—and optimized the diagnostic criteria for this disease. Russian experts discussed all aspects of the new nomenclature and the possibilities of its use in the Russian Federation and came to the following conclusions and recommendations: use optimized diagnostic criteria for NAFLD in the clinical practice of Russian physicians and include them in these guidelines; for working with official medical documentation, use the already familiar terms "NAFLD" and "NASH" due to the necessity of using ICD-10; for scientific purposes, new terms with agreed and approved translation into Russian can be used [5]. For example, MASLD for NAFLD, metabolic dysfunction-associated steatohepatitis (MASH) for NASH.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The initial understanding of NAFLD pathogenesis as a "two-hit" theory [6] has been replaced by the concept of multifactorial pathogenesis, which includes parallel processes such as insulin resistance (IR), impaired autophagy, lipotoxicity, inflammation, cytokine and adipokine imbalance, activation of innate immunity and the microbiota, as well as environmental and genetic factors [7, 8]. One of the key factors in the development of NAFLD is the impairment of systemic energy balance, characterized by an excess of substrates, predominantly carbohydrates and fatty acids. The main sources of free (non-esterified) fatty acids (FFAs) delivered to the liver include their increased release from adipocytes (about 60%), hepatic carbohydrate conversion (de novo lipogenesis, 26%), and excessive dietary fat intake (14%) [9, 10].

Insulin resistance. Insulin resistance (IR) is characterized by a decrease in the sensitivity of peripheral tissues (muscles, adipose tissue, liver) to insulin. Epidemiological studies demonstrate a correlation between a high-carbohydrate diet and NAFLD. Excessive carbohydrate intake and elevated blood glucose levels exert detrimental effects on cells (glucotoxicity). The development of IR in the liver is accompanied by increased gluconeogenesis and decreased glycogenogenesis, leading to hyperglycemia [11–13]. IR leads to reduced glucose uptake by adipocytes and muscles, while hepatocytes can secrete dipeptidyl peptidase-4 (DPP-4), which promotes adipose tissue inflammation and the development of IR [12, 13]. Metabolic dysregulation of adipocytes creates conditions for excessive triglyceride (TG) lipolysis, the release of FFAs into the bloodstream, and their entry into the liver [14]. In hepatocytes during NAFLD, excess glucose and fructose enhances de novo lipogenesis [15]. Unlike glucose, however, the involvement of fructose in this process is not regulated by glycolysis [16].

Adipose tissue is not only the primary source of FFAs, but also an endocrine organ that secretes adipokines with systemic regulatory effects. Leptin and adiponectin, produced by visceral adipocytes, influence NAFLD by regulating appetite, fat composition, insulin sensitivity, and inflammation. In NAFLD, there is a decrease in adiponectin production and an increase in leptin synthesis, while in NASH, serum leptin levels are elevated compared to healthy individuals [17, 18]. Hyperleptinemia and low levels of the soluble leptin receptor (leptin-binding protein) indicate peripheral tissue leptin resistance and are detected in patients with NAFLD to a greater extent than in obese individuals without hepatic steatosis [19].

Excessive production of pro-inflammatory cytokines by visceral adipose tissue macrophages is crucial in the development of systemic inflammation in obesity. Activated macrophages secrete cytokines and chemokines (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and CCL2 (C-C Motif Chemokine Ligand)), contribute to the development of local IR leading to lipid metabolism dysregulation, and can promote systemic IR [20, 21]. Pro-inflammatory mediators activate key transcription factors, such as JNK (Jun N-terminal kinase) and NF-κB (nuclear factor kappa B), leading to hepatocyte damage, inflammation, and stimulation of fibrogenesis [22].

Autophagy impairment and lipotoxicity. Autophagy is a universal intracellular catabolic process (including lipophagy, mitophagy, reticulophagy, and pexophagy) in which dysfunctional or excess organelles (e.g., mitochondria, peroxisomes, endoplasmic reticulum, lipid droplets) are identified, tagged, delivered to lysosomes, and engulfed for degradation into building blocks, followed by utilization for cellular needs. The specificity of selective autophagy makes it a crucial process in reducing hepatocyte injury caused by the abnormal accumulation of dysfunctional organelles in the pathogenesis of NAFLD, a function that no other system can replace [23].

The direct link between autophagy and apoptosis makes it a key player in the regulation of cell life and death. One of the central roles in these processes is assigned to the beclin-1 protein, which triggers the formation and maturation of the phagophore. In a complex with the Bcl-2 protein (B-Cell Leukemia/Lymphoma 2, an intracellular protein factor and apoptosis regulator), it inhibits autophagy, whereas disruption of this interaction due to the competitive formation of the Bcl-2/Bax bond (BCL2 Associated X Protein, bcl-2-like protein 4) leads to its activation. Thus, beclin-1 in a complex with Bcl-2 functions as a molecular switch between autophagy and apoptosis [24]. Cellular stress, in particular the excessive influx of FFAs into the hepatocyte and the accumulation of TGs, initially stimulates the adaptive capacities of the hepatocyte and subsequently leads to their exhaustion [25]. As a result, the cell develops an adenosine triphosphate (ATP) deficiency and accumulates adenosine monophosphate (AMP), which activates adenosine monophosphate-activated protein kinase (AMPK). This enzyme triggers a complex autophagy process, which in NAFLD aims to eliminate lipid droplets (lipophagy), damaged mitochondria (mitophagy), and TG synthesis intermediates (diacylglycerol, etc.).

Furthermore, AMPK modulates hepatic lipogenesis through several mechanisms: phosphorylation (and inactivation) of transcription factors SREBP-1c (sterol regulatory element-binding transcription factor 1, which induces the expression of a family of genes involved in glucose utilization and fatty acid synthesis and plays a role in the development of hepatic steatosis), SREBP-2 (transcription factor 2, a key regulator of cholesterol (chol) metabolism; activation of its gene leads to increased uptake and synthesis of cholesterol), as well as ChREBP (Carbohydrate-Responsive Element-Binding Protein; in adipose tissue, it induces de novo lipogenesis from glucose, whereas in the liver, its induction by glucose promotes glycolysis and lipogenesis, playing a role in the development of type 2 diabetes mellitus (DM), dyslipidemia, and hepatic steatosis). AMPK activity is reduced in patients with NAFLD, and its agonists may be effective in treating this disease [26–30].

A major influence on AMPK-dependent autophagy is exerted by the hyperactivation of the serine-threonine kinase mTOR (mechanistic target of rapamycin), which inhibits lysosomal biogenesis and autophagy processes. This occurs under the influence of cytosolic Ca²⁺ overload and oxidative stress induced by the lipotoxicity of FFAs, diacylglycerols, ceramides, lysophosphatidylcholine, and cholesterol. As a result, endoplasmic reticulum stress and lysosomal dysfunction develop, lipid peroxidation (LPO) processes are exacerbated, and hepatocyte injury or death occurs [31, 32].

Oxidative stress and mitochondrial dysfunction. Increased FFA influx into the liver leads to enhanced peroxisomal α- and β-oxidation, as well as ω-microsomal oxidation involving cytochrome P-450, which initiates lipid peroxidation. In addition, increased utilization of FFAs in mitochondria is accompanied by the production of highly active oxygen species and compounds that damage these organelles, causing mitochondrial dysfunction and progressive energy depletion [33]. As a result, major energy-dependent processes in hepatocytes are suppressed, the functioning of enzymatic and non-enzymatic components of antioxidant defense is impaired, and further generation of new free radicals and lipid hydroperoxides occurs, which, under the catalytic activity of iron ions, form secondary free-radical products. Such an oxidative cascade is characterized by hepatocyte injury and leads to the development of inflammation, hepatic stellate cell (HSC) activation, and fibrogenesis [34].

Immune mechanisms of inflammation and fibrogenesis. Upon an excessive flux of FFAs or other pathogens (such as endotoxins) from the intestine into the liver, Kupffer cells phagocytose pathogenic factors and present them via pattern recognition receptors (PRRs) [35]. These receptors include Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs) [36]. Inflammasomes via the NLR protein activate a cascade of events, ultimately leading to the activation of the transcription factor NF-κB [37, 38]. Kupffer cells differentiate into M1 or M2 phenotypes depending on the external inducer. The M1 phenotype produces pro-inflammatory cytokines TNF-α, IL-1, and IL-12, whereas M2 (the alternative macrophage phenotype) is capable of stimulating the secretion of IL-4, IL-10, and transforming growth factor beta (TGF-β), which possess anti-inflammatory properties [39]. IL-6 and TNF-α produced by activated macrophages are responsible for the progression of NASH [40, 41].

T-helper lymphocytes are also involved in the implementation of liver inflammation. Following immune activation, T cells differentiate into Th1, Th2, and Th17 effector cells. NASH is characterized by an excess of Th1-derived cytokines, such as interferon (IFN)-γ, and a deficiency of Th2-produced cytokines—IL-4, IL-5, and IL-13 [42]. Th17 cells, which produce IL-17, infiltrate the liver in NASH and enhance inflammation and fibrosis by affecting macrophages and HSCs [9]. Cytotoxic CD8⁺ T cells in the liver in NAFLD produce IFN-γ and TNF-α, leading to increased steatosis, IR, inflammation, and HSC activation [43]. In turn, HSCs transform into an activated phenotype (myofibroblasts), proliferate intensively, and produce collagen, fibronectin, laminin, hyaluronic acid, matrix metalloproteinases, and their tissue inhibitors [44]. The accumulation of fibrillar collagens (types I and III) in the space of Disse causes capillarization of sinusoids, disruption of liver angioarchitecture, local hypoxia, and the progression of fibrogenesis.

Gut–liver axis. Among the commensal organisms inhabiting the human gut, 4 major phyla dominate: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. The microbiota plays a vital role in maintaining intestinal barrier integrity and gut permeability. The gut microbiota also actively participates in bile acid biokinetics with the formation of their metabolites, thereby indirectly influencing the development of NAFLD via bile acid receptors such as the farnesoid X receptor (FXR), membrane-type bile acid receptor (TGR5, GPBAR1), and vitamin D receptor (VDR), which modulate nutrient metabolism and insulin sensitivity [45]. Disruption of the microbiota composition can damage the intestinal epithelium and disrupt tight junction proteins, leading to the translocation of bacteria, bacteria-produced ethanol, and endotoxins from the gut into the portal circulation [46, 47]. This induces hepatic inflammation and fibrogenesis, contributing to liver injury [48, 49].

Genetic aspects. In the course of large-scale genetic studies (genome-wide association studies) conducted in various countries predominantly among Caucasians, dozens of genes have been identified whose polymorphisms may be associated with the development of NAFLD and NASH [50, 51].

The most compelling data in most populations have been obtained regarding the association with an unfavorable course of NAFLD (development of NASH, fibrosis, and HCC) of the rs738409 polymorphism in the PNPLA3 gene (patatin-like phospholipase domain-containing protein 3, adiponutrin gene) and the rs58542926 polymorphism in the TM6SF2 gene (transmembrane 6 superfamily member 2). These mutations are hypothesized to be relevant to the Russian population, but studies have been conducted only in individual regions of the Russian Federation [52–55].

Thyroid hormones and NAFLD. Thyroid hormones modulate hepatic glucose and lipid metabolism. The role of hypothyroidism in the development and progression of NAFLD is being discussed [56, 57], as impaired activation of thyroid hormone receptors (THR-β) promotes increased steatosis through a number of mechanisms, including mitochondrial dysfunction [58].

Thus, the pathogenesis of NAFLD encompasses a whole complex of pathological processes occurring in parallel. This diversity of pathological mechanisms characterizes NAFLD as a disease requiring a multidisciplinary approach, and the treatment strategy should aim to correct the various aspects of pathological changes in the patient.

1.3 Epidemiology of the Disease or Condition

NAFLD is currently the most common chronic non-communicable liver disease, affecting 25% to 30% of adults in most countries [59, 60]. In Russia, the epidemiology of NAFLD has been studied in several trials. According to the multicenter DIREG (2007) and DIREG-2 (2015) studies among outpatients, the prevalence of NAFLD in the Russian Federation is increasing: 27% and 37.3%, respectively [61, 62].

According to the ESSE-RF-2 epidemiological study (2022), the prevalence of NAFLD in Russia was 38.5% for men and 26.6% for women [63]. Similar data on the prevalence of NAFLD in the Russian Federation and the trend towards its increase were demonstrated in a recent meta-analysis of 5 studies with a total sample size of 96,680 patients [64].

The prevalence of NASH is difficult to assess accurately because a definitive diagnosis requires a liver biopsy—an expensive and invasive procedure that is not always available. According to literature data, NASH occurs in 3–5% of the global population, the majority of whom suffer from multiple comorbidities [65]. At the same time, according to a prospective study of a large middle-aged cohort, NASH occurs in 14% of cases and is also significantly associated with the presence of type 2 diabetes mellitus and obesity [66]. The development of fibrosis in NASH determines its clinical outcomes: approximately 20% of patients develop cirrhosis and/or HCC, which serves as the main cause of their death. Using a Markov mathematical model accounting for the prevalence of type 2 diabetes mellitus and obesity, it was shown that the global prevalence of NASH will increase to 15–56% by 2030 [67]. Accordingly, healthcare workers' efforts, including those in the Russian Federation, can and must influence this negative scenario.

NAFLD is closely associated with various comorbidities: obesity occurs in 51.34% (95% confidence interval [CI] 41.38–61.20) and 81.83% (95% CI 55.16–94.28) of patients with NAFLD and NASH, respectively; type 2 diabetes mellitus occurs in 22.51% (95% CI 17.92–27.89) and 43.63% (95% CI 30.28–57.98) of patients with NAFLD and NASH, respectively; the prevalence of hyperlipidemia/dyslipidemia was 69.16% (95% CI 49.91–83.46) and 72.13% (95% CI 54.59–84.78) among patients with NAFLD and NASH, respectively; and arterial hypertension (AH) was present in 39.34% (95% CI 33.15–45.88) and 67.97% (95% CI 56.31–77.74) of patients with NAFLD and NASH, respectively. Metabolic syndrome (MetS) is detected in 42.54% (95% CI 30.06–56.05) and 70.65% (95% CI 54.64–82.79) of patients with NAFLD and NASH, respectively [67].

Worldwide, recent decades have seen a trend toward an increasing proportion of NAFLD in the structure of etiological factors of liver cirrhosis [68], as well as HCC, including cases developing without the cirrhosis stage [69].

1.4 Features of Coding the Disease or Condition

K75.8 – Other specified inflammatory liver diseases.

K76.0 – Fatty (change of) liver, not elsewhere classified.

1.5 Classification of the disease or condition

Two main phenotypes (forms) of NAFLD are distinguished:

– steatosis;

– NASH.

Since the diagnosis of NASH requires histological verification, the term NAFLD is used predominantly in the remainder of these clinical guidelines when formulating indications for diagnostic and therapeutic measures.

Management issues for patients with cirrhosis in the context of NASH are covered in clinical guidelines dedicated to liver cirrhosis [70], do not have significant features in NASH, and are therefore not discussed in these clinical guidelines.

1.6 Clinical presentation of the disease or condition

NAFLD is characterized by a mild or asymptomatic course. The most common complaints include hepatogenic fatigue/asthenia, which occurs in more than 70% of patients, and a sensation of heaviness or discomfort in the right upper quadrant [71, 72]. Frequently, complaints of patients with NAFLD are determined by comorbid conditions (obesity, etc.). A manifest clinical picture is observed with the development of NASH and cirrhosis with its complications (see clinical guidelines "Liver Cirrhosis and Fibrosis", ID 715).

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of NAFLD is established:

1) upon confirmation of hepatic steatosis (according to imaging studies or liver tissue histology);

2) in the presence of 1 or more cardiometabolic risk factors:

– body mass index (BMI) > 25 kg/m² or waist circumference > 94 cm in men, > 80 cm in women (or above the upper limit of normal if the patient belongs to an ethnic group for which different norms of BMI and/or waist circumference are established);

– fasting glucose > 5.6 mmol/L or postprandial glucose > 7.8 mmol/L or glycated hemoglobin (Hb_A1c) > 5.7% or previously diagnosed type 2 diabetes mellitus or ongoing treatment for type 2 diabetes mellitus;

– blood pressure ≥ 130/85 mm Hg or pharmacotherapy for previously diagnosed AH;

– plasma triglycerides ≥ 1.70 mmol/L or lipid-lowering therapy;

– plasma high-density lipoprotein (HDL) cholesterol < 1.0 mmol/L in men and < 1.3 mmol/L in women or lipid-lowering therapy;

3) upon exclusion of other leading causes of fatty liver disease (Table 1) [2, 73].

Table 1. Causes of fatty liver disease

2.1 Complaints and Anamnesis

Taking the history and anamnesis should aim to identify cardiometabolic risk factors necessary for the diagnosis of NAFLD, associated diseases, and their complications (overweight / obesity, hypertension, type 2 diabetes mellitus, dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD)); evaluating lifestyle habits, diet, and alcohol consumption.

2.2 Physical Examination

Comments: Objective examination generally reveals signs of overweight or obesity with a male (abdominal) fat distribution pattern. It is necessary to evaluate indicators such as BMI, waist, and hip circumferences. Palpation and percussion of the abdomen in NAFLD patients without signs of significant fibrosis may reveal a moderate hepatomegaly, with a rounded edge and doughy consistency. With advanced fibrosis, the liver becomes firm, and at the cirrhosis stage, hepatic stigmata, splenomegaly, and ascites may be observed [74].

2.3 Laboratory Diagnostics

Comments: Abnormalities in the complete blood count in patients with NAFLD most commonly occur at the stage of severe fibrosis/cirrhosis and manifest as cytopenia (predominantly varying degrees of thrombocytopenia). Bicytopenia or pancytopenia may be present, reflecting hypersplenism syndrome [74, 75]. Complete blood count parameters are also used to calculate non-invasive fibrosis indices.

Comments: The blood biochemistry panel may show elevated serum transaminase activity (ALT and AST), GGT (elevation of this enzyme may be isolated), ALP, and bilirubin levels. A number of major clinical studies have shown that the correlation between elevated ALT activity and the severity of inflammatory response and liver fibrosis is not always evident [77]. In NAFLD, serum transaminase activity typically does not exceed the upper limit of normal (ULN) by more than 4–5 times. Either ALT or AST may predominate, but the AST/ALT ratio does not exceed 1.3 [78]. Taking this ratio into account can be useful in differential diagnosis with alcoholic liver disease (in which the AST/ALT ratio is usually greater than 2). GGT activity in patients may be elevated, but generally no more than 2–3 times, and in some patients, this may be the only abnormality in the biochemical profile. ALP activity increases less frequently and usually does not exceed normal values by more than 2 times [75].

Comments: According to the diagnostic criteria for NAFLD, cardiometabolic risk factors include fasting blood (plasma) glucose ≥ 5.6 mmol/L (100 mg/dL) or glycemia ≥ 7.8 mmol/L (≥ 140 mg/dL) during a glucose tolerance test, or Hb_A1c ≥ 5.7% (39 mmol/mol) [2]. It is advisable to screen patients with NAFLD for type 2 diabetes mellitus and other carbohydrate metabolism disorders by determining fasting blood (plasma) glucose or glycated hemoglobin, or by performing an OGTT with 75 g of glucose according to the values and rules provided in the clinical guidelines "Type 2 diabetes mellitus in adults" [79]. To assess insulin resistance, the HOMA-IR index is used, calculated by the formula: HOMA-IR = fasting plasma insulin (µIU/mL) × fasting plasma glucose (mmol/L) / 22.5. A HOMA-IR value ≥ 2.5 indicates the presence of insulin resistance. It should be borne in mind that the diagnostic value of the index in patients with overt diabetes mellitus is reduced [2, 80].

Comments: According to the diagnostic criteria for NAFLD, cardiometabolic risk factors include: elevated triglycerides ≥ 1.70 mmol/L or ≥ 150 mg/dL, decreased HDL-C ≤ 1.0 mmol/L (≤ 40 mg/dL) in men and ≤ 1.3 mmol/L (50 mg/dL) in women [2]. Patients with NAFLD need to be tested for total cholesterol, LDL-C, and HDL-C to stratify the risk of cardiovascular complications in accordance with the clinical guidelines "Disorders of lipid metabolism" [83].

Comments: The prevalence of CKD is estimated at 20–55% in patients with NAFLD compared to 5–30% in patients without NAFLD. There is a growing body of evidence indicating an association between NAFLD and CKD due to shared risk factors for their development, while data also support an independent association between these conditions. If signs of CKD are detected via screening tests, further evaluation of patients is carried out in accordance with the clinical guidelines "Chronic kidney disease in adults" [92]. Patients with NAFLD and type 2 diabetes mellitus are prone to developing urinary tract infections [92, 93].

Comments: Uric acid plays a certain role as a predictor of NAFLD development. Its level has an independent association with NAFLD. Furthermore, elevated uric acid levels are associated with obesity, insulin resistance, the severity of liver damage, and the risk of a more severe course of NAFLD. A uric acid level above 360 µmol/l should be considered as a marker of hyperuricemia [93].

Comments: As part of clinical practice, other liver diseases most common in the adult population are always ruled out in these patients. These include chronic hepatitis B and C, for which screening tests are HBsAg and total antibodies to hepatitis C virus (anti-HCV IgG and anti-HCV IgM), respectively; autoimmune hepatitis (screening tests include serum class G immunoglobulins or gamma-globulins, with elevated levels being clinically significant); hereditary hemochromatosis (screening test: transferrin saturation percentage > 45%); and Wilson's disease (screening test: serum ceruloplasmin < 20 mg/dL) [96–98].

2.4 Instrumental Diagnostics

Diagnosis of Steatosis

Comments: Ultrasound signs of NAFLD include:

• diffuse hyperechogenicity of the liver parenchyma and heterogeneity of its structure;

• blurring and/or enhancement of the vascular pattern;

• distal attenuation of the echo signal [99, 100].

Conventional transabdominal ultrasound is most commonly used in the diagnosis of hepatic steatosis because it is widely available, safe, inexpensive, and well-established. In a meta-analysis of 34 studies (2,815 patients with suspected liver disease), the pooled sensitivity and specificity of ultrasound in detecting steatosis were 85% (95% CI 80–89%) and 94% (95% CI 87–97%), respectively (compared with liver biopsy results). The main limitations of ultrasound are that it can detect steatosis only when fat accumulation exceeds 12.5–20%, its accuracy is reduced in obese patients, and it depends to some extent on operator experience [101]. Nevertheless, ultrasound remains the most widely used and acceptable method for detecting steatosis [102].

Comments: The ability to quantify steatosis by measuring ultrasound echo wave attenuation was implemented on the FibroScan device and is termed the "controlled attenuation parameter" (CAP). The method demonstrates high sensitivity and specificity, especially in detecting minimal and moderate steatosis. In severe steatosis, results were more heterogeneous due to the influence of age, elevated BMI, and differences in cutoff value determination [104]. A meta-analysis of 16 studies with individual data from 2,346 patients compared the results of CAP steatosis quantification with histological data. For obese patients with excessive subcutaneous adipose tissue, it was important to use the appropriate probe during the examination. The M or XL probe was selected according to established guidelines. The XL probe was recommended for 1,050 patients, 930 (89%) of whom had NAFLD; the result was good for detecting steatosis of any degree compared to no steatosis (AUROC 0.819; 95% CI 0.769–0.869), but suboptimal for distinguishing mild from higher-grade steatosis (S0–S1 vs. S2–S3; AUROC 0.754; 95% CI 0.720–0.787). According to this meta-analysis, the optimal threshold value (Youden index) for detecting steatosis as such in NAFLD patients is 294 dB/m (sensitivity 0.790, specificity 0.740) [103]. CAP is a promising method for rapid and standardized detection of steatosis when using the XL probe. However, for its quantification, it is inferior to magnetic resonance imaging (MRI-PDFF).

Comments: The quantitative MRI-PDFF method makes it possible to estimate the amount of fat in the liver. The most accurate result is obtained using the Proton Density Fat Fraction (PDFF) value. It is the PDFF value that corresponds with high accuracy to the quantitative and volumetric fat content in the liver. In a recent meta-analysis (6 studies involving 635 patients with histologically confirmed NAFLD), the pooled AUROC values for MRI-PDFF for steatosis amounts of > 5%, > 33%, and > 66% were 0.98, 0.91, and 0.90, respectively. The pooled sensitivity and specificity were 93% and 94%, 74% and 90%, and 74% and 87%, respectively [105]. Despite the high accuracy of MRI-PDFF in quantifying steatosis, the high cost and limited availability of the method limit its use in routine clinical practice.

Diagnosis of Steatohepatitis

Comments: Currently, no non-invasive methods for diagnosing steatohepatitis (inflammation) have been developed, and liver biopsy remains the gold standard. To establish a diagnosis of NASH, histological examination of liver tissue and simultaneous detection of steatosis, ballooning degeneration, and lobular inflammation are required [107–110]. Other histological changes may also be present, but they are not considered necessary for diagnosis (portal inflammation, polymorphonuclear infiltrates, Mallory–Denk bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, and megamitochondria). Perisinusoidal and pericentral fibrosis are also common but are not part of the diagnostic criteria; as for the term "borderline NASH," it is poorly defined and best avoided. The term "burned-out NASH" describes the regression of severe disease (steatosis, inflammation, or ballooning degeneration) in patients with metabolic syndrome risk factors. All other methods, such as CK-18 (cytokeratin 18), combinations of clinical variables, combinations of clinical variables with the PNPLA3 I148M variant, etc., as well as imaging methods proposed for the non-invasive diagnosis of NASH, do not reflect inflammation and are not recommended for clinical use for this purpose, as they either show conflicting results, lack a sufficient number of confirmatory studies, or present difficulties in obtaining certain variables for broad and simple reproducibility [106].

Thus, liver biopsy currently remains the reference standard for diagnosing NASH in patients with NAFLD. In addition to determining NAFLD characteristics such as the presence of steatosis, fibrosis stage, and severity of lobular inflammation, liver biopsy in some cases allows for the identification/exclusion of other causes of liver injury. In 2005, based on a consensus of morphological experts (CRN), the NAFLD Activity Score (NAS) was proposed for assessing NAFLD, which is a modification of previously used Brunt and Matteoni scales from 1999 and allows morphological changes to be scored (from 0 to 8): the severity of hepatic steatosis, intralobular (lobular) inflammation, hepatocyte ballooning degeneration, and fibrosis stage [110] (Appendix G1). This scale can also be used to evaluate the efficacy of NAFLD treatment, as it allows for the determination of reliable dynamics in morphological changes during therapy over a relatively short period of time [77, 111].

In 2012, the SAF (Steatosis, Activity, and Fibrosis) scoring system was proposed for histological evaluation of the liver in morbid obesity and subsequently validated in 2014; it includes characteristics such as the severity of steatosis (S – steatosis), ballooning degeneration, and lobular inflammation (A – activity), and the stage of liver fibrosis (F – fibrosis) – see Appendix G2 (the evaluation result is recorded as an index such as S1A2F3, S2A1F1, etc.) [109]. The SAF scoring system has been further developed to allow the use of the FLIP (Fatty liver inhibition of progression) algorithm aimed at standardizing and improving the quality of morphological diagnosis [109].

In the absence of a liver tissue biopsy, but in the presence of convincing non-invasive data regarding a progressive disease course (e.g., elevated surrogate markers of inflammation – transaminases, data from non-invasive methods indicating fibrosis, etc.), experts consider it acceptable to establish a diagnosis of "probable NASH".

Diagnosis of fibrosis

Comments: The most validated and reliable among non-proprietary tests (which are publicly available) are NFS and FIB-4. In clinical practice, the following threshold values (cut-off points) are used to determine whether a patient with NAFLD has severe fibrosis or not: 1.3 for FIB-4 and –1.455 for NFS (high sensitivity), and 3.25 for FIB-4 and 0.676 for NFS (high specificity).

NFS and FIB-4 have the following advantages: 1) both tests are based on simple variables widely available in clinical practice; 2) their results can be easily obtained at the bedside using free online calculators; 3) they have good overall diagnostic accuracy for severe fibrosis, as demonstrated by a meta-analysis (36 studies involving 9,074 patients) – AUROC 0.80 for FIB-4 and 0.78 for NFS, respectively, with an NPV of ≥ 90% [112]. Disadvantages of NFS and FIB-4 include: 1) the risk of false-positive criteria for severe fibrosis – PPV < 70%; 2) in a third of cases, an indeterminate result (between the upper and lower thresholds); 3) presumably, the effect of older age on diagnostic accuracy. This issue was resolved by adopting a higher threshold value for individuals over 65 years of age: 2.0 for FIB-4 and 0.12 for NFS [113]. The predictive value of calculated indices in elderly individuals and patients with diabetes mellitus is likely lower [114].

Comments: Among proprietary serum markers of fibrosis, FibroMeterTM, FibroTest®, and ELFTM are the most common. Among all listed tests, currently only FibroTest® is available in the Russian Federation. In general, the diagnostic accuracy of proprietary non-invasive serum tests (FibroMeterTM, FibroTest®, and ELFTM) for diagnosing fibrosis is satisfactory, but their widespread use in clinical practice is limited by high cost and limited availability [102, 112, 366, 367].

Comments: Transient elastography is the most widely used examination to determine liver tissue stiffness, backed by the largest volume of data in patients with NAFLD. A large meta-analysis (17 studies using an M-probe involving 2,642 patients; 3 studies using an XL-probe involving 318 patients) reports good diagnostic accuracy of this method for detecting severe fibrosis, i.e., stage 3 fibrosis (AUC 0.87 for the M-probe and 0.86 for the XL-probe) and cirrhosis (AUC 0.92 for the M-probe and 0.94 for the XL-probe) [112]. In clinical practice, there is no complete consensus regarding the liver stiffness thresholds for diagnosing severe fibrosis in NAFLD; recent data suggest a value of ≥ 8 kPa, with a sensitivity of 93% [115]. Transient elastography results can be influenced by a number of factors, such as inflammatory activity (results are unreliable when ALT levels are high).

Comments: Measurement of liver tissue stiffness using shear wave techniques available on modern ultrasound systems is comparable in accuracy to transient elastography, although data in patients with NAFLD are limited. The most accurate results for liver stiffness determination are obtained by magnetic resonance elastography, but this method is expensive, has limited availability, and is used primarily in clinical trials.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The treatment of NAFLD should pursue two goals:

1) prevention of liver disease progression, regression of steatosis, steatohepatitis, and fibrosis;

2) reduction of cardiometabolic risk factors.

Fundamentally, NAFLD treatment is divided into non-pharmacological measures (diet and physical activity) and pharmacotherapy.

3.1 Non-pharmacological therapy for NAFLD

3.1.1 Physical activity

• Regular physical activity is recommended for patients with NAFLD to reduce liver fat content [117, 118].

Level of Evidence BGrade of Recommendation 2Level of Evidence B (Grade of Recommendation 2).

Comments: The World Health Organization (WHO) has developed physical activity recommendations for adults aimed at preventing a number of diseases, including those associated with NAFLD [117]. To reduce liver fat content, patients with NAFLD are recommended to engage in moderate-intensity aerobic physical activity for at least 150–300 min per week or vigorous-intensity aerobic physical activity for at least 75–150 min per week, or to combine moderate- and vigorous-intensity physical activity throughout the week. At least twice a week, aerobic exercise is recommended to be supplemented with moderate- or vigorous-intensity physical activity (strength exercises) targeting all muscle groups [117, 118]. Intensity is the pace of physical activity or the amount of effort required to perform a given type of activity or exercise per unit of time (for example, a walking speed of 5 km/h). It can be characterized as follows: how hard a person is working to perform a particular type of activity.

Moderate-intensity physical activity increases heart rate, but a conversation can be comfortably maintained during its performance. Examples include brisk walking, dancing, gardening, household chores, active games and sports with children, walking pets, etc.

Vigorous-intensity physical activity (e.g., running, aerobics, lap swimming, fast cycling, uphill hiking, etc.) significantly increases heart rate and respiratory rate and causes sweating [117].

Physical activity recommendations must take into account the patient's individual physical fitness and comorbidities. Since 95% of patients with NAFLD are overweight or obese, it is useful to consider the provisions of the clinical guidelines on "Obesity" [119].

Systematic reviews and meta-analyses have established that physical exercise reduces liver fat content even in the absence of significant weight loss [118, 120–123]. A study involving 115 patients with NAFLD and prediabetes demonstrated that intensive aerobic exercise for 30–60 minutes 2–3 times a week for 6 months or more leads to a 24.4% reduction in liver fat content [124]. A systematic review showed the efficacy of aerobic and resistance exercise 3 times a week for 12 weeks in reducing liver fat in patients with NAFLD [120]. In a study of patients with NAFLD where liver fat content was assessed by MRI and spectroscopy, high-intensity aerobic exercise (stationary cycling for 30–40 minutes 3 times a week) was shown to significantly reduce liver fat content compared to controls (sedentary individuals) [125, 126].

For patients who experience difficulties performing aerobic exercise (e.g., poor cardiorespiratory fitness), resistance exercise (strength training) can be recommended, as it also helps improve lipid metabolism and promotes a more favorable course of NAFLD [120]. In general, patients should be encouraged to pay as much attention to physical activity as possible. Optimal physical activity in terms of duration and intensity should be selected on an individual basis [127].

3.1.2 Diet

Dietary modifications remain the most effective non-pharmacological tool for both the treatment of NAFLD and weight loss.

• Patients with NAFLD are recommended a balanced diet adhering to the principles of the Mediterranean dietary pattern in order to reduce liver fat content [128–130].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comments: The Mediterranean diet is a scientific concept that primarily implies a macronutrient composition (50–60% carbohydrates, 30% fats, 20% proteins) and a balanced approach. This type of diet contains a high amount of natural antioxidants, biological components with anti-inflammatory activity, and has a low glycemic index. The Mediterranean diet involves the use of olive oil as the main source of fat and is characterized by the consumption of large amounts of vegetables, fruits, nuts, legumes, whole grains, fish, and seafood; conversely, it features a low consumption of dairy products, meat, and meat products. Molecular mechanisms of favorable health effects have been proven for such components of the Mediterranean diet as polyphenols, carotenoids, oleic acid, polyunsaturated fatty acids (PUFAs), dietary fiber, and quercetin [128, 131]. Two cross-sectional studies showed that adherence to the Mediterranean diet inversely correlates with the risk of developing NAFLD and NASH [132, 133].

A randomized crossover study demonstrated that following a Mediterranean diet for 6 weeks compared to a standard low-fat high-carbohydrate diet reduced liver fat content by 39% versus 7%, respectively, and also decreased HOMA-IR regardless of changes in body weight [134]. Adherence to the Mediterranean dietary pattern is one of the independent prognostic factors positively affecting the severity of NAFLD course [135]. The advantage of this diet is the ability to follow it without harm to health for an indefinitely long period of time and to adapt it to any geographical region and the patient's personal food preferences [127].

• Patients with NAFLD are recommended to avoid consuming products containing added fructose to reduce liver fat accumulation [136, 137].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

Comments: The consumption of added fructose (represented predominantly in sweetened beverages) contributes to the development of NAFLD. Meta-analyses of controlled studies show that the intake of added fructose leads to a significant increase in liver fat and elevated ALT. The negative effect of added fructose may be partly related to an increase in dietary calorie content. No negative impact on NAFLD has been established for natural sources of fructose (honey, fruits, dried fruits) provided that the adequate energy value of the diet is maintained [136, 137].

• Patients with NAFLD without overweight / obesity are recommended regular physical activity in accordance with WHO guidelines [117] and a balanced diet adhering to the principles of the Mediterranean dietary pattern [128, 363 ] to reduce insulin resistance, prevent cardiovascular disease and sarcopenia, and decrease visceral fat.

GGR BLEL 3Grade of Recommendation B (Level of Evidence 3).

Comments: The management of patients with NAFLD and normal body weight represents a clinical challenge. In such cases, a thorough differential diagnosis must be performed to exclude rare causes of fatty liver disease (monogenic diseases, drug-induced effects, etc.). The general recommendation for weight loss is unacceptable for them in most cases, although a randomized controlled trial (RCT) showed that lifestyle modification achieved NAFLD remission in normal-weight patients with a 3–5% weight loss [1, 138, 139]. Dietary changes and physical exercise in this group of patients can be useful in terms of reducing insulin resistance, increasing muscle mass, and preventing cardiovascular diseases and their complications. These patients are advised to reduce their intake of alcohol, added fructose, saturated fats, simple carbohydrates, and ultra-processed foods [140].

• Patients with NAFLD are recommended to refrain from consuming any amount of alcohol to prevent fat accumulation and the progression of liver fibrosis [141].

GGR BLEL 3Grade of Recommendation B (Level of Evidence 3).

Comments: It is currently a well-known fact that, in addition to cardiometabolic risk factors, alcohol consumption in doses exceeding 20 and 30 g of ethanol per day for women and men, respectively, also leads to steatosis, steatohepatitis, and liver fibrosis. Moreover, alcohol intake can act both as the main factor causing the development of alcoholic fatty liver disease and as an additional link potentiating disease progression [142, 143]. This was convincingly demonstrated in a systematic review, the authors of which also concluded that any doses of alcohol, even supposedly safe ones, affect disease progression [141].

Recommendations for weight loss in obese patients are presented in Section 3.3.2 "Management of NAFLD Combined with Obesity".

3.2 Pharmacological therapy for NAFLD

Currently, despite the progress achieved in understanding the pathogenesis, clinical course, and prognosis of NAFLD, issues of pharmacotherapy for this disease are still under discussion, and studies of drugs targeting various metabolic pathways are ongoing: regulation of carbohydrate and lipid metabolism, the thyroid pathway, autophagy and apoptosis, etc. The main targets in the treatment of NAFLD are steatosis (which serves as an independent cardiometabolic risk factor), inflammation, and fibrosis [144, 145]. All phenotypes of NAFLD are associated with an increased risk of developing cardiovascular disease, endocrine pathology, and other metabolic disorders [146]. A feature of NAFLD is its multisystem nature and comorbidity, which influences therapeutic approaches. Based on this, two main goals of NAFLD therapy can be formulated:

1) reduction of lipid content in hepatocytes, decrease in inflammation activity, prevention of development / slowing the progression of fibrosis;

2) reduction of the patient's cardiometabolic risks associated with excess lipids in hepatocytes and (or) inflammation and (or) fibrosis.

Accordingly, the optimal medicinal product should contribute to the simultaneous achievement of these goals, ensure the optimization of economic costs, and possess a high safety profile.

Various medicinal products are used for the treatment of NAFLD, which can be conditionally divided into 2 groups:

1) drugs with a hepatotropic effect, including those with a registered indication for NAFLD; some of them have a pleiotropic effect and simultaneously influence the cardiovascular system, lipid, and carbohydrate metabolism;

2) drugs registered for the treatment of comorbid conditions typical of NAFLD with an additional hepatotropic effect. For example, statins—HMG-CoA reductase inhibitors—for the treatment of hypercholesterolemia and dyslipidemia; glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, semaglutide**) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors (dapagliflozin**, empagliflozin**, ipragliflozin**) for the treatment of type 2 diabetes mellitus.

This section discusses hepatotropic drugs (group 1 drugs). The use of group 2 drugs is described in the section on the treatment of comorbid conditions. The efficacy of hepatotropic drugs is assessed primarily by the dynamics of ALT levels (a surrogate marker of inflammation), as well as by non-invasive methods that semi-quantitatively or quantitatively assess liver fat content – CAP or MRI-PDFF (if available), using non-invasive fibrosis assessment methods (calculated indices, elastography) (see section 2 "Diagnosis of the Disease or Condition").

Serum transaminases (ALT and AST) serve as a simple and reliable laboratory sign of hepatocellular injury (inflammation), and their decrease guides the assessment of treatment efficacy in patients with any etiology of liver injury. ALT is more specific for hepatocyte injury compared to AST [147]. A positive correlation has been proven between serum transaminase levels and mortality from digestive system diseases (of which 89% are liver diseases), oncological diseases, and CVD [148, 149]. Elevated ALT > 30 IU/L in men and > 19 IU/L in women correlate with increased mortality from liver diseases and DM [147, 150]. Individuals with NAFLD and increased serum ALT activity have an increased calculated risk of developing coronary artery disease (CAD) according to the Framingham Risk Score, especially women [151].

Currently, there are only isolated studies in the treatment of NAFLD that include the analysis of histological data before and after treatment (paired biopsies) and almost no works assessing the long-term course of the disease based on "hard" endpoints (life expectancy, mortality, etc.). At the same time, a large number of randomized and observational studies, as well as their meta-analyses, have been conducted in which the efficacy of NAFLD pharmacotherapy was evaluated using surrogate markers of inflammation (serum transaminase levels, GGT) and fibrosis. This is understandable, since liver biopsy is an invasive, expensive, and not universally available procedure. In clinical practice, the efficacy of liver disease therapy is assessed by the dynamics of ALT levels (a surrogate marker of inflammation), while modern non-invasive techniques allow evaluating the dynamics of steatosis and fibrosis [1]. The choice of a drug for the treatment of NAFLD depends on the clinical manifestations of the disease, its phenotype, and the features of its course, and is determined by the attending physician individually for each patient.

• Pharmacotherapy for NAFLD is recommended in combination with lifestyle modification measures (physical activity and proper nutrition), especially in cases of their insufficient efficacy, barriers to implementation, and/or a progressive course of the disease [152, 153].

GCR BLOE 1Grade of Recommendation B (Level of Evidence 1).

Comments: Lifestyle modification (physical activity and proper nutrition) is the basis of NAFLD treatment. According to studies, < 10% of patients achieve weight loss within a year with a structured approach to physical activity, of which less than half maintain the achieved result for 5 years [154]. In addition, meta-analyses of recent years indicate the uncertainty of the impact of lifestyle interventions in patients with NAFLD on long-term prognosis and disease outcomes due to the relatively short (no more than 2 years) duration of the conducted studies and their heterogeneity [152, 153, 155].

Comments: In a clinical study in patients with histologically proven NASH and paired liver biopsies, the use of UDCA** at a daily dose of 13–15 mg/kg of body weight for 12 months led to a statistically significant decrease in the severity of liver steatosis and a reduction in ALT, AST, GGT, and ALP levels compared to the comparison group [158]. Similar data were demonstrated in another study with 6-month use of UDCA** [159].

In one study, the use of high doses of UDCA** (#28–35 mg/kg/day, a dose exceeding that recommended in the instructions) for 12 months by patients with biopsy-proven NASH led to a significant decrease in ALT levels: by the end of the study, normalization of this parameter was observed in one out of five patients and only in approximately one out of twenty in the placebo group. At the same time, the results did not depend on the patients' weight dynamics. Also, in the UDCA** group, a significant decrease in FibroTest® scores was noted compared to placebo (potential antifibrotic effect). No serious adverse events were observed [160].

According to a domestic meta-analysis performed in 2018 based on 4 studies with a total sample size of 510 people, UDCA** in NAFLD had a high safety profile, while no effect on the histological and biochemical parameters of the disease was proven [161]. However, a systematic review and two later meta-analyses showed that the use of UDCA** leads to a decrease in serum transaminases (ALT, AST) and GGT and reduces liver steatosis [156, 162, 163]. A prospective observational multicenter non-comparative study "USPEKH", performed in real-world clinical practice, showed that treatment with UDCA** at a dose of 15 mg/kg of body weight for 6 months in patients with NAFLD leads to a statistically significant (p < 0.001) decrease in the activity of ALT, AST, GGT, blood concentrations of total cholesterol, TG, LDL, and the Fatty Liver Index (FLI). Progression of fibrosis, assessed by the NFS index, was not noted [164].

Molecular studies have shown that UDCA** exerts its effect on reducing liver steatosis and inflammation through the modulation of the autophagy effect, being a stimulator of one of the main intracellular sensors of homeostasis – AMPK [165], whose activity is reduced in liver steatosis [25]. In patients with NAFLD, stimulation of lipophagy and mitophagy via UDCA** leads to a decrease in liver fat, a reduction in lipotoxicity, and, accordingly, inflammation. Autophagy is closely linked to apoptosis via Bcl-2/beclin-1 proteins, and the anti-apoptotic effect of UDCA** is well known [166]. The reduction of steatosis and inflammation prevents the development and progression of fibrosis. In preclinical studies, it was shown that UDCA** reduces the severity of liver steatosis also as a TGR5 ligand [167]. In an experimental study on an NAFLD model, it was proven that UDCA** is able to prevent the development of both steatosis and fibrosis without having a significant effect on hepatocyte ballooning degeneration. UDCA** helps reduce de novo hepatic lipogenesis, increases tissue sensitivity to insulin, restores bile acid synthesis, and participates in the positive modulation of the GPBAR1 bile acid receptor activity [168].

The recommended duration of UDCA** administration is at least 6 months; the optimal dose used in most clinical studies is 13–15 mg/kg/day.

Comments: #Vitamin E is used for the treatment of NAFLD in patients with histologically confirmed progressive NASH and is included in a number of clinical guidelines for the management of patients with NAFLD, which are based on the results of the PIVENS randomized trial [1, 174–177]. #Vitamin E at a dose of 800 IU/day was used for 22 months and exceeded placebo in efficacy in patients with NASH regarding its effect on steatosis, inflammation, and ballooning degeneration, but had no significant effect on fibrosis [169]. In cases where NASH was combined with type 2 diabetes, histological activity was affected only by the combination of #vitamin E (800 IU/day) with #pioglitazone (45 mg/day) for 18 months; an effect on fibrosis was also not noted [170]. A large controlled study showed a reduction in the risk of death, liver transplantation, or disease decompensation with the use of #vitamin E at a dose of 800 IU/day for more than 2 years in patients with histologically proven NASH and advanced stages of the disease (bridging fibrosis, cirrhosis). The average patient follow-up duration was 5.6 years [173]. According to meta-analyses, #vitamin E improves laboratory parameters, and reduces histological manifestations of steatosis and inflammation [171, 172].

A potential safety concern of high doses of #vitamin E—an increased risk of all-cause mortality and hemorrhagic stroke—was identified in meta-analyses published in 2005 and 2013 [178, 179], but a later meta-analysis in 2014 did not confirm these findings [180]. The association between #vitamin E intake and an increased risk of prostate cancer in men is also being discussed [181]. However, none of these studies evaluated the safety of #vitamin E specifically in patients with NAFLD.

In addition, potential interactions of high doses of #vitamin E (> 300 mg/day) with concomitantly prescribed acetylsalicylic acid**, warfarin**, tamoxifen**, and cyclosporine**, leading to altered activity of the latter, should be considered [182]. Accordingly, prescribing high doses of #vitamin E should be approached with caution and take into account the patient's medical history. The potential benefit of prescribing #vitamin E in patients with NAFLD and DM is under discussion [56, 170]. The recommended duration of treatment is at least 12 months.

Comments: Hepatogenic weakness/fatigue is a symptom that affects patients' quality of life and limits their adherence to recommendations for increasing physical activity. The effect of ademetionine** on hepatogenic weakness/fatigue in various liver diseases, including NAFLD, has been demonstrated in systematic reviews and a meta-analysis [183, 184]. A reduction in the proportion of patients with hepatogenic weakness/fatigue during drug administration was observed in a single-center comparative study in patients with NASH and in a multicenter prospective non-comparative observational study in patients with NAFLD in routine clinical practice [185, 186]. Reduction in weakness/fatigue is observed with short-term (2–4 weeks) intake of ademetionine**, while increasing the duration of the course increases the proportion of patients experiencing a reduction in this symptom [183, 184]. The recommended duration of treatment is at least 4 weeks.

Comments: In preclinical studies, bicyclol prevented the elevation of transaminases, hepatic lipid accumulation, and fibrogenesis by inhibiting inflammatory and oxidative stress signaling pathways in a high-fat diet model [189–191].

According to a meta-analysis that included 12 studies on NAFLD with a total sample size of 1008 individuals, bicyclol as monotherapy and in combination with other drugs had a positive effect on laboratory parameters of inflammatory activity and lipid metabolism, promoting a decrease in ALT, AST, TG, and TC levels [187].

Similar results were obtained in a cohort study involving 93 individuals, where 24-week administration of bicyclol, in addition to improving laboratory parameters, was also accompanied by a reduction in signs of fibrosis and steatosis according to fibroelastometry [192]. In an open-label non-comparative observational study of 51 patients with chronic diffuse liver diseases of any etiology and elevated serum transaminase levels (including 29 patients with NAFLD), the use of bicyclol led to a decrease/normalization of ALT levels, which decreased statistically significantly from baseline as early as 2 weeks of treatment [188]. According to experts, moderate ALT elevation is defined as a range from 3- to 5-fold increase above the ULN, and marked elevation as more than a 5-fold increase above the ULN. The recommended duration of treatment is no more than 24 weeks.

Comments: The fixed combination of inosine + meglumine + methionine + nicotinamide + succinic acid** as an infusion solution has a hepatotropic effect, implemented through the ability of succinic acid to correct mitochondrial dysfunction developing in NAFLD by maintaining succinate dehydrogenase activity and increasing macroergic compound production. Methionine is an essential amino acid that plays a key role as a regulator of a number of cellular functions. Inosine is capable of interacting with adenosine A2a and A3 receptors with their subsequent activation, which leads to a reduction in hepatocyte injury caused by hypoxia and FFAs, and also exerts a systemic anti-inflammatory effect by modulating NF-κB activity. Nicotinamide acts as a coenzyme for NAD-dependent enzyme systems, an acceptor and carrier of protons in the electron transport chain, thereby indirectly stimulating cellular respiration, energy production, cellular regeneration, biosynthesis, and the metabolism of proteins, carbohydrates, and lipids. In addition, nicotinamide is involved in sirtuin-mediated processes (DNA repair, mitochondrial biogenesis, apoptosis, inflammation). Meglumine, which is part of the drug, ensures better penetration of succinic acid through biological membranes [193].

In small RCTs, this combination drug (400 ml once daily for 10–11 days) in patients with NASH led to an improvement in laboratory parameters of cytolysis and cholestasis [195, 196]. In a comparative study, the inclusion of such a fixed combination in the treatment regimen of patients with NAFLD in the form of steatohepatitis led to more rapid relief of asthenovegetative and dyspeptic syndromes and a reduction in the severity of biochemical manifestations of cytolytic and cholestatic syndromes [194].

The fixed combination "inosine + meglumine + methionine + nicotinamide + succinic acid**" is prescribed at 400 ml intravenously drip once daily for 10 days at the inpatient treatment stage. Indications for inpatient treatment are outlined in Section 6, "Organization of Medical Care".

Comments: According to studies evaluating the morphological features of NAFLD, histological signs of cholestasis in this disease occur in 27.0–30.1% of cases, although they are much less frequently reflected in the laboratory cholestatic profile [197, 198]. Secondary cholestasis in NAFLD indicates a more active disease course, the development of its late stages, and a worse prognosis [198, 199].

A decrease in endogenous ademetionine synthesis in chronic liver diseases and NAFLD contributes to the development of intrahepatic cholestasis by reducing the activity of the bile acid transporter (Bile Salt Export Pump (BSEP)) and disrupting hepatocyte membrane integrity [200]. The duration of ademetionine** intake in progressive NAFLD should be at least 4 months; the maximum duration of the course is not limited [185]. A two-step therapy scheme is possible: parenteral administration at a dose of 5–12 mg/kg/day followed by a transition to oral administration at a dose of 10–25 mg/kg/day, but not exceeding 1600 mg/day.

Comments: A study of liver biopsy samples from patients with NAFLD demonstrated a significant decrease in urea and glutamine synthesis activity compared to controls [205], and dysregulation of urea cycle genes and protein expression was established in experimental models of NASH [206]. The development of hyperammonemia has been demonstrated in a significant proportion of patients at pre-cirrhotic stages of NAFLD [203, 204, 207].

Among ornithine preparations, ornithine (L-ornithine-L-aspartate, LOLA) in oral form has the strongest evidence base; it dissociates into its constituent amino acids and stimulates urea synthesis in periportal hepatocytes and glutamine formation in perivenous hepatocytes, skeletal muscles, and the brain. It is hypothesized that LOLA, in addition to its ammonia-lowering effect in NAFLD, may exert a beneficial effect through mechanisms of metabolic transformation into L-glutamine, L-arginine, and glutathione, reducing lipid peroxidation, exerting an anti-inflammatory effect, and improving portal hemodynamics [201, 202].

In a parallel-controlled clinical trial, a 12-week course of oral LOLA treatment resulted in a dose-dependent improvement in laboratory liver function tests and tomographic characteristics in patients with NASH [208]. The results of experimental studies also suggest a direct beneficial effect of LOLA on skeletal muscle in NASH models: the drug prevents the development of myosteatosis and qualitative muscle changes [209], and also improves exercise tolerance in this pathology [210]. The recommended duration of treatment is at least 12 weeks. 

Combined use of hepatotropic drugs

There are pathogenetic rationales for the combined use of a number of hepatotropic drugs in the form of both non-fixed and fixed combinations, which either expand the spectrum of their hepatotropic action or achieve a unidirectional increase (additivity, summation, potentiation) of a particular pharmacological effect. Despite the fact that the evidence base of most clinical studies conducted is not very high, it can nevertheless serve as a rationale for choosing the combined use of a number of drugs in routine clinical practice [211]. At the same time, only those combinations that have been studied in NAFLD or NASH should be used, taking into account additional indications and contraindications.

Comments: In a comparative study in patients with NASH, the addition of UDCA** (12–15 mg/kg/day) to #vitamin E (800 IU/day) for 2 years led to a statistically significant increase in blood adiponectin levels, which correlated with a decrease in the severity of hepatic steatosis [214]. In another study, repeat biopsy analysis showed that only against the background of combination therapy with UDCA** and #vitamin E was there a decrease in the histological activity index with the regression of hepatic steatosis [212]. Long-term (4 years, range 1–12 years) use of the combination of UDCA** (mean 16.6 mg/kg/day) and #vitamin E (mean 555 IU/day) in patients with NASH made it possible to reduce ALT, AST, and GGT in 65–80% of patients and achieve an improvement in the histological picture of the liver in the majority with a low (5%) rate of side effects requiring drug withdrawal [213]. The recommended dose of the combination of #vitamin E and UDCA** preparations should not exceed the maximum doses of drugs prescribed separately: for #vitamin E – no more than 800 IU/day, UDCA** – 10–15 mg/kg/day.

3.3 Treatment of NAFLD and associated conditions

3.3.1 Treatment of NAFLD in combination with type 2 diabetes mellitus

Comments: Lifestyle modification in the combination of type 2 diabetes and NAFLD should comply with the clinical guidelines for "Type 2 diabetes mellitus in adults" [79]. Dietary principles in NAFLD and type 2 diabetes are similar and do not contradict each other. The degree of weight loss is associated with the severity of improvement in the histological parameters of NAFLD and NASH. A 12-month prospective study showed that all patients who lost more than 10% of their body weight had improved histological parameters: the NAS score, with 90% of patients showing resolution of NASH and 45% having fibrosis regression [216].

In addition to simple weight loss, adhering to a diet (with restricted carbohydrate and increased protein content) for 6 weeks allows for better glycemic control, leads to a decrease in serum triglyceride levels, and reduces the severity of hepatic steatosis (assessed by MR spectroscopy) in patients with type 2 diabetes [215].

Given the fact that type 2 diabetes and NAFLD share common pathogenetic features, it is not surprising that some methods used to treat type 2 diabetes are also actively used to treat NAFLD. Currently, numerous studies have been conducted aimed at finding a hypoglycemic drug that could affect the pathological changes in NAFLD and NASH. Such a drug should reduce body weight, reduce cardiovascular events, prevent the development of late stages of NAFLD, and also have low cost, long-term safety, and improve quality of life.

Comments: Incretin mimetics, including glucagon-like peptide-1 receptor agonists, are used to treat type 2 diabetes and obesity. They stimulate glucose-dependent insulin secretion, reduce de novo lipogenesis, and lead to a decrease in body weight, insulin resistance, and serum transaminase levels. The use of glucagon-like peptide-1 receptor agonists is a very attractive and promising method for treating NAFLD, but it is not yet known whether this group of drugs has a direct effect on hepatocytes, directly reducing hepatic steatosis and inflammation, or whether the effect is achieved through weight loss.

One of the most studied drugs of this group for the treatment of patients with type 2 diabetes and NAFLD is #liraglutide. According to a meta-analysis of 8 studies, this drug led to a decrease in both BMI and waist circumference, as well as liver fat content, as assessed by non-invasive methods, and surpassed other hypoglycemic drugs in the magnitude of effects (#metformin**, insulins and their analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors) [217]. Similar results were obtained in a systematic review with meta-analysis [218]. In addition, #liraglutide administration contributed to a decrease in serum transaminases and bilirubin, as well as an improvement in the non-invasive fibrosis index APRI (Aspartate Aminotransferase to Platelet Ratio Index) [217].

Studies of another drug from the group of glucagon-like peptide-1 receptor agonists, #semaglutide**, have also been initiated. Phase II clinical trial of #semaglutide** in patients with NASH and fibrosis has now been completed. #Semaglutide** provided a statistically significant regression of NASH, but no statistically significant difference between the drug and placebo regarding the reduction of fibrosis was found [219]. Despite the absence of convincing data on the reduction of liver fibrosis according to histological examination, individual meta-analyses report a decrease in liver stiffness against the background of #semaglutide** use [220–222].

Studies on the efficacy of #liraglutide and #semaglutide** in patients with type 2 diabetes noted a reduction in cardiovascular and cerebrovascular events [223, 224], which was associated, among other things, with weight loss [225]. The recommended duration of #liraglutide use (1.8–3.0 mg/day) is at least 48 weeks, and for #semaglutide** (2.4 mg/week) – from 48 to 72 weeks according to studies.

Comments: Thiazolidinediones are a class of antidiabetic drugs that increase tissue sensitivity to insulin and participate in the regulation of lipid metabolism. One of the representatives of this class, #pioglitazone at a dose of 30–45 mg/day compared to placebo in several studies and meta-analyses, demonstrated efficacy in the treatment of NASH regarding the improvement of liver panel laboratory tests and the histological picture (severity of steatosis and inflammatory activity) in patients with NASH with and without type 2 diabetes [176, 227, 228]. A systematic review of studies on the effects of #pioglitazone therapy reported a decrease in signs of hepatic steatosis in patients with NAFLD and type 2 diabetes, which was also confirmed histologically [228]. Despite the lack of a clear effect on fibrosis, in a number of studies, liver stiffness assessed by transient and MR elastometry decreased, but there was no decrease in serum type IV collagen 7S levels, which suggests that the decrease in stiffness occurs mainly due to the fat fraction. Also, in this work, a significant positive effect on laboratory markers of inflammation (decrease in ALT, AST, GGT activity) and dyslipidemia (decrease in LDL and increase in HDL levels) was noted in patients with NAFLD and type 2 diabetes receiving #pioglitazone [172].

The negative effects of #pioglitazone treatment include weight gain, an increased long-term risk of bladder cancer, and osteoporosis. The drug is also not recommended for patients with chronic heart failure (CHF) and those receiving high doses of insulins and their analogues or amlodipine** [229]. Both the European and American associations for the study of the liver consider the use of #pioglitazone for the treatment of NASH only in selected groups of patients, taking into account the risks of developing the aforementioned conditions. The recommended dose of the drug is 30–45 mg per day, with a duration of administration of at least 24 weeks. A contraindication to prescribing #pioglitazone is an ALT level exceeding the ULN by 2.5 times [230].

Comments: Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) are a relatively new class of antidiabetic drugs that inhibit glucose reabsorption in the proximal renal tubules via an insulin-independent mechanism. In addition to their primary function, these drugs have been shown to exhibit a number of pleiotropic effects, including cardio- and nephroprotection. Recently, the ability of SGLT2 inhibitors to exert a positive effect on the course of NAFLD has been attracting attention [232]. According to a meta-analysis of 10 RCTs involving 573 patients with NAFLD and type 2 diabetes mellitus, the use of SGLT2 inhibitors (predominantly #dapagliflozin**, #ipragliflozin**) for 12 weeks or more led to a more significant decrease in ALT, AST levels, and a reduction in the FIB-4 index compared to other oral hypoglycemic agents. A positive effect on weight loss, reduction of visceral fat, and liver fat content assessed by MRI-PDFF was also noted [233]. A large meta-analysis yielded similar results, but when assessing fibrosis using the type IV collagen 7S marker rather than the FIB-4 index, no statistically significant difference was found between the SGLT2 inhibitor group and the control group, which included other hypoglycemic agents. The study also noted a significant positive effect on LDL-C levels with SGLT2 inhibitor use for more than 24 weeks compared to the control group. Another important conclusion of the work is the confirmation of the high safety profile of SGLT2 inhibitors. Despite known adverse drug reactions in the form of an increased risk of urogenital infections, the authors report a non-significant statistical difference between the studied groups [234].

According to 2 meta-analyses including 16 RCTs (699 patients) and 18 RCTs (1330 patients), the use of SGLT2 inhibitors (#dapagliflozin**, #empagliflozin**, #ipragliflozin**) for 12–24 weeks led to a statistically significant reduction in non-invasive markers of steatosis (by MRI) and fibrosis (FIB-4 index, liver stiffness, CAP parameter, serum type IV collagen 7S level) [235, 236]. The recommended dose of #dapagliflozin** is 5–10 mg per day, and of #empagliflozin** is 10–25 mg/day. The drugs are intended for long-term use both as monotherapy and as part of combination treatment.

Comments: A large systematic review with meta-analysis of clinical studies demonstrated the effect of ursodeoxycholic acid**, used in various doses for durations ranging from 6 weeks to 2 years, on glycemic parameters [237]. Thus, a meta-analysis of 7 studies utilizing 8 ursodeoxycholic acid** treatment arms showed a statistically significant reduction in fasting glucose levels following such therapy (weighted mean difference –3.30 mmol/l). A meta-analysis of 2 treatment arms showed a statistically significant reduction in glycated hemoglobin concentration (weighted mean difference –0.41%). In addition, a meta-analysis of 4 treatment arms also revealed a statistically significant decrease in plasma insulin levels without a substantial effect on HOMA-IR. The results of this meta-analysis showed that ursodeoxycholic acid** significantly reduces fasting plasma glucose, glycated hemoglobin, and insulin concentrations, indicating its positive effect on glucose homeostasis.

In 2021, an RCT with 240 participants was published, evaluating the effects of #empagliflozin** at a dose of 25 mg and ursodeoxycholic acid** at a dose of 250 mg/day over 6 months. Thus, the #empagliflozin** group showed a more significant reduction in steatosis according to MRI-PDFF, and a more pronounced decrease in triglyceride and glucose levels compared to the ursodeoxycholic acid** group. At the same time, ursodeoxycholic acid** was superior to #empagliflozin** in terms of reducing liver fibrosis indices and insulin resistance. The effect on BMI and serum transaminase levels in both groups was comparable. These results led the authors to conclude that both drugs possess sufficient safety and efficacy and can be used for the treatment of NAFLD in patients with type 2 diabetes mellitus [238]. The recommended dose of ursodeoxycholic acid** is 13–15 mg/kg/day. The duration of administration is at least 6 weeks.

3.3.2 Treatment of NAFLD in combination with obesity

Non-pharmacological therapy

• Lifestyle modification (dietary correction, increased physical activity) is recommended for patients with NAFLD and obesity as mandatory measures to reduce body weight, steatosis, inflammation, and liver fibrosis [239].

GCR BLeveled Evidence 1Grade of Recommendation B (Level of Evidence 1).

Comments: Lifestyle modification (diet and physical activity) serves as the basis of treatment for both NAFLD and obesity and is most effective when conducted under medical supervision. The management of patients with NAFLD and obesity should also be guided by the clinical guidelines for "Obesity" [119]. Weight loss in obesity has a favorable effect on the severity of steatosis and the activity of steatohepatitis both in short-term studies and according to meta-analyses [239, 240], although the results of high-quality prolonged follow-ups are currently lacking [155, 239, 240].

Aerobic exercise and strength training effectively reduce liver fat content. Exercises are selected individually, taking into account the patient's preferences to enhance adherence [174]. Resistance exercises may be more appropriate than aerobic exercises for NAFLD patients with poor cardiorespiratory fitness or for those unable to tolerate or participate in aerobic exercise. Both aerobic and resistance exercises reduce hepatic steatosis in NAFLD when performed at the same frequency and duration (40–45 min/session 3 times a week for 12 weeks) [120].

An important condition for the effective treatment of patients with NAFLD and obesity is the simultaneous adherence to dietary recommendations and increased physical activity. Thus, according to an RCT involving 80 people, the combination of a calorie-restricted diet and moderate physical activity led to a more significant reduction in hepatic steatosis by MRI-PDFF, weight loss, fat mass reduction, waist circumference, and lipid profile parameters than physical activity and diet separately [241]. At the same time, drastic calorie restriction and rapid weight loss can lead to the progression of fibrosis and an increase in serum transaminase levels. Slow weight loss is recommended – by 0.5–1 kg per week [175, 242, 243].

To achieve the target weight loss, maintain adherence to weight reduction, and control the achieved weight, it is advisable to use a number of measures at the physician's discretion, such as faster initial weight loss, personalized feedback, a positive attitude from medical personnel, support from the social environment (friends and family members), and participation in structured weight loss programs [244, 245].

Pharmacological therapy

Comments: In the absence of a clinically significant weight loss with non-pharmacological methods, and to increase the effectiveness of obesity treatment, pharmacotherapy can be used: liraglutide (a glucagon-like peptide-1 (GLP-1) receptor agonist) 0.6–1.8 mg/day, or orlistat (a peripheral-acting anti-obesity drug) 120 mg/day, or sibutramine (a central-acting anti-obesity drug) 10–15 mg/day. This allows for more effective weight loss, facilitates adherence to dietary recommendations, helps in developing new dietary habits, and contributes to the long-term maintenance of reduced body weight [174, 175, 246, 247]. These medications are recommended for the treatment of obesity in accordance with the clinical guidelines for "Obesity" [119].

Comments: The prevalence of cholelithiasis in obese patients is higher than in the general population, while rapid weight loss, especially when following a diet with severe fat restriction, increases the risk of gallstone formation, symptomatic cholelithiasis, and cholecystectomy [251, 252]. Meta-analyses have shown that the use of UDCA** during a weight-loss diet prevents the risk of gallstone formation [248], and UDCA** treatment after bariatric surgery reduces the risk of symptomatic cholelithiasis [249, 250, 253]. Furthermore, in a study on the prevention of cholelithiasis during weight loss using UDCA, 84% of patients had NAFLD [365].

Surgical treatment

In obese patients (BMI > 35 kg/m²) with NAFLD who have not achieved positive results from lifestyle modifications and/or pharmacotherapy, bariatric surgery may be performed (see section 3.4 "Surgical treatment").

3.3.3 Treatment of NAFLD in combination with dyslipidemia and ASCVD

NAFLD, even at the steatosis stage, is an independent risk factor for cardiovascular disease, regardless of type 2 diabetes mellitus, dyslipidemia, or obesity. In patients with NAFLD and dyslipidemia, target lipid profile levels are determined by cardiovascular risk. When prescribing lipid-lowering therapy to patients with NAFLD, target lipid levels are selected in accordance with the clinical guidelines for "Lipid Metabolism Disorders" [83].

Comments: HMG-CoA reductase inhibitors (statins) inhibit hepatic cholesterol synthesis and are widely used in the treatment of dyslipidemia and ASCVD for the primary and secondary prevention of cardiovascular diseases and their complications. NAFLD is frequently combined with dyslipidemia and other cardiometabolic disorders such as arterial hypertension, coronary artery disease, chronic heart failure, and rhythm and conduction disturbances [93, 256]. Therefore, statins are frequently prescribed to such patients. Statin doses are calculated in accordance with the clinical guidelines for "Lipid Metabolism Disorders" [83, 257].

According to systematic reviews and meta-analyses, HMG-CoA reductase inhibitors have a favorable safety profile in NAFLD and inherently contribute to reducing ALT, AST, and GGT levels [255, 258, 259]. This is particularly relevant for patients with elevated liver enzymes prior to initiating HMG-CoA reductase inhibitor therapy. A number of studies have demonstrated that HMG-CoA reductase inhibitors in patients with NASH and dyslipidemia lead to a reduction in steatosis, inflammation, and fibrosis [255, 258–261].

When prescribing lipid-lowering therapy, transaminases are monitored 8–12 weeks after initiation. If ALT exceeds 3 times the upper limit of normal (ULN), the drug is discontinued. In patients with NASH and baseline elevated ALT levels, the baseline ALT level should be used instead of the ULN [262].

Comments: In a randomized prospective clinical trial of patients with hypercholesterolemia, it was shown that when simvastatin** (20 mg/day) or atorvastatin** (20 mg/day) therapy was ineffective, their combination with UDCA** was statistically significantly more effective compared to doubling the dose of HMG-CoA reductase inhibitors in terms of their effect on total cholesterol and LDL-C levels [265].

The multicenter observational study RAKURS evaluated the efficacy and safety of the combined administration of statins and UDCA** in patients with chronic liver diseases and cardiovascular diseases who required statin therapy. According to the study results, the addition of UDCA** to statin therapy led to a statistically significantly better effect compared to HMG-CoA reductase inhibitor monotherapy: target LDL-C levels among patients receiving HMG-CoA reductase inhibitors and UDCA** were achieved by 37% of patients by the end of the 6-month therapy period, compared to 20% among those receiving HMG-CoA reductase inhibitors alone. It was also noted that the combination of UDCA** with HMG-CoA reductase inhibitors prevents statin-induced increases in serum transaminases [263].

In a secondary analysis of the RAKURS study, patients with NAFLD (89%) were isolated from the general participant group. In these patients, statin monotherapy during the first month of treatment was characterized by a positive trend in lipid metabolism parameters without adverse effects on liver function tests. In turn, combination therapy with HMG-CoA reductase inhibitors and UDCA** for 6 months led to a significant decrease in total cholesterol and LDL-C levels compared to HMG-CoA reductase inhibitor monotherapy [264].

In an experimental model of NAFLD, it was demonstrated that the combination of UDCA**, #rosuvastatin, and #ezetimibe leads to a statistically significant decrease in ALT levels, exerting anti-apoptotic and anti-fibrotic effects compared to the combination of #rosuvastatin + #ezetimibe [266].

Research results have shown that UDCA** is able to potentiate the effect of HMG-CoA reductase inhibitors, which is especially relevant for patients with ineffectiveness of low doses of HMG-CoA reductase inhibitors and intolerance to their high doses. The recommended dose of UDCA** is 10–15 mg/kg/day.

Comments: #Ezetimibe blocks the NPC1L1 (Niemann-Pick C1-Like 1) sterol transporter on the apical membrane of enterocytes, which reduces dietary cholesterol absorption and may lead to certain positive dynamics of histological signs of NAFLD. In patients with NAFLD, the favorable cardiovascular effects of HMG-CoA reductase inhibitors are preserved during monotherapy and in combination with #ezetimibe [267]. According to a meta-analysis of 6 clinical studies, #ezetimibe reduced transaminase and GGT levels, decreased liver steatosis and hepatocyte ballooning degeneration, but did not affect inflammation and fibrosis [267]. In another meta-analysis, #ezetimibe, conversely, reduced the activity of steatohepatitis but did not affect the severity of steatosis [268]. Such discrepancies in the conclusions of the two meta-analyses may be dictated by the small number of studies evaluating liver histology. In the open-label RCT ESSENTIAL, the combination of #ezetimibe with an HMG-CoA reductase inhibitor reduced liver fat content assessed by MRI-PDFF [269].

When using the combination of #ezetimibe with #HMG-CoA reductase inhibitors, monitoring of laboratory parameters (ALT, AST) is also required. In case of elevated transaminases, further decisions on discontinuing therapy (the entire combination or only HMG-CoA reductase inhibitors) and/or adjusting drug doses are made in accordance with the current instructions for statins. If liver cirrhosis develops, the use of #ezetimibe should be avoided upon the appearance of signs of hepatic decompensation (Child–Pugh class B–C).

Comments:  #Omega-3-triglycerides, including other esters and acids (omega-3 PUFAs) are medications used to lower TG levels. Preclinical studies have demonstrated the ability of #omega-3-triglycerides, including other esters and acids to reduce hepatic lipogenesis and improve insulin sensitivity [273]. The REDUCE-IT study involving 8,179 patients proved the positive effect of eicosapentaenoic acid (#omega-3-triglycerides, including other esters and acids) combined with a statin on "hard" endpoints—cardiovascular events [274]. In a double-blind, placebo-controlled RCT, administration of eicosapentaenoic acid (#omega-3-triglycerides, including other esters and acids) at a dose of 2.4 g/day in patients with NAFLD, although it did not affect the histological parameters of NASH, reduced TG levels compared to placebo without increasing serious side effects [275]. At the same time, another study, in which liver fat content was determined using magnetic resonance spectroscopy, which provides a more accurate overall assessment of hepatic fat content, showed that a course of #omega-3 acid ethyl esters—a combination of docosahexaenoic acid and eicosapentaenoic acid at a dose of 4 g/day—reduced liver fat content [276]. According to meta-analyses, #omega-3-triglycerides, including other esters and acids can reduce liver fat content, liver enzymes, and blood lipids [270–272].

Only medicinal products of #omega-3 acid ethyl esters can be recommended, since dietary supplements containing #omega-3 PUFAs lack approved clinical indications, proven therapeutic efficacy, pharmaceutical and biological equivalence, and cannot be used to replace prescription drugs [277]. The dose and duration of administration are regulated by the clinical guidelines for "Lipid Metabolism Disorders" [83].

Comments: Fibrates are used in the treatment of dyslipidemia, and only #fenofibrate** may be used in combination with statins. There are theoretical prerequisites and experimental data suggesting that #fenofibrate** may have a positive effect on NAFLD [279]. Large-scale studies investigating the effect of fibrates on NAFLD have not been conducted. In a small RCT with paired biopsies, 48-week therapy with #fenofibrate** led to a decrease in the proportion of patients with elevated levels of aminotransferases, glucose, alkaline phosphatase, and GGT, and a reduction in ballooning degeneration without affecting the degree of steatosis, lobular inflammation, or fibrosis [278]. Studies examining the efficacy of fibrates in dyslipidemia combined with NAFLD showed no increase in adverse effects, while some observed a decrease in transaminases [278–280].

When prescribing #fenofibrate** during the first year of therapy, monitoring of transaminase and creatinine levels is required every 3 months; co-administration with statins increases the risk of rhabdomyolysis.

Comments: Currently, a large body of research has accumulated on the use of EPL in the treatment of NAFLD. Most of these studies are small-scale, yet they form the scientific basis for the use of this class of drugs. In studies, EPL are mainly used as part of combination therapy: combined with hypoglycemic or hypolipidemic therapy, or together with ursodeoxycholic acid (UDCA)** or probiotics. This is because EPL not only possess their own pharmacological activity but also act as bioenhancers (biopotentiators). When used as a combination or co-administered with other medicinal substances, they can potentially provide higher bioavailability (pharmacokinetic enhancing) and, consequently, an increase in biological effect (pharmacodynamic enhancing) [283, 284]. The adjuvant effect of EPL was demonstrated in an observational study involving 2,843 patients with hepatic steatosis and cardiometabolic comorbidity (type 2 diabetes mellitus, hypercholesterolemia, hypertension, obesity, or overweight). In 69.6% of patients after 3 months of EPL intake and in 81.4% of patients after 6 months of therapy, there was an improvement in ultrasound characteristics of the liver against the background of baseline pharmacotherapy with the addition of the drug (1800 mg/day) [281]. According to a systematic review with meta-analysis, the use of EPL combined with hypoglycemic therapy led to a more significant reduction in ALT, cholesterol, and TG levels, as well as an improvement in the ultrasound picture of the liver in patients with NAFLD combined with obesity and type 2 diabetes mellitus, although this meta-analysis has methodological flaws [282].

Other lipid-lowering agents (#proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK inhibitors]) appear to be promising drugs for NAFLD. They may exert a beneficial effect on the course of NAFLD, but high-quality studies have not yet been performed. A small RCT in 40 patients with heterozygous familial hypercholesterolemia demonstrated the resolution of previously diagnosed NAFLD and NASH after 1 year of treatment with other lipid-lowering agents (#proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK inhibitors]), specifically #evolocumab** or #alirocumab**. No signs of steatosis, inflammation, or fibrosis were detected [285]. Other lipid-lowering agents (#proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK inhibitors]) are considered safe drugs in NAFLD [286], but further research is required regarding the efficacy and safety of drugs of this class in patients with NAFLD.

3.3.4 Treatment of NAFLD in combination with chronic kidney disease

There is a growing body of evidence indicating an association between NAFLD and chronic kidney disease (CKD) due to shared risk factors for their development, while data also indicate an independent association between these conditions. The presence of NAFLD is associated with an increased incidence of proteinuria, a more significant decrease in the estimated glomerular filtration rate (eGFR), and the development and progression of CKD [287, 288]. In patients with type 2 diabetes mellitus, the presence of NAFLD is associated with an increased frequency of CKD development, regardless of age, sex, and hypertension [289].

Risk factors for CKD in individuals with NAFLD that are unrelated to liver function include older age, diabetes mellitus, hypertension, baseline reduced estimated glomerular filtration rate, smoking, thyroid dysfunction (hypothyroidism due to fat accumulation, hyperthyroidism due to the production of reactive oxygen species), and alcohol consumption. A number of factors are involved in the development of CKD in patients with NAFLD, the key factor being systemic low-grade inflammation triggered via several inflammatory cascades [290–294].

Comments: Preliminary studies demonstrated a positive effect of #losartan**, #telmisartan, and #valsartan on histological indicators of necroinflammation and laboratory markers in NASH, with #telmisartan being more effective than #valsartan [297–299]. The effect of RAS blockade using ACE inhibitors and ARBs on the course of NAFLD has also been evaluated in small RCTs. Specifically, in a small open-label comparative study involving patients with NAFLD, diabetes mellitus, and hypertension, therapy with the ARB #telmisartan, which also exhibits PPAR (Peroxisome Proliferator-Activated Receptor) agonist activity, resulted in a reduction in liver fat content assessed by CT and a decrease in serum FFA levels compared to #losartan** [296]. In another study, long-term (more than 1 year) use of ACE inhibitors or ARBs in patients with stage C3 CKD, end-stage kidney disease, and after kidney transplantation was associated with a lower prevalence of NAFLD and lower liver stiffness compared to patients not taking these medications [293]. Experimental models have shown the ability of ACE inhibitors and ARBs to inhibit hepatic fibrogenesis [300]. In a cohort study including 12,327 patients with NAFLD receiving ACE inhibitors or ARBs with a follow-up of at least 5 years, use of ACE inhibitors, but not ARBs, was associated with a reduction in liver-related events (liver cancer and cirrhosis complications), with a greater reduction in patients with CKD than without it [295].

Comments: Sodium-glucose cotransporter 2 inhibitors reduce afferent arteriolar vasoconstriction and can provide nephroprotection by reducing glomerular hyperfiltration, preventing oxidative stress and inflammation in proximal tubular cells, as well as via other mechanisms [303, 304]. Evaluation of the nephroprotective potential demonstrated that in patients with CKD, #dapagliflozin** compared with placebo is capable of reducing the combined risk of a sustained decline in the estimated glomerular filtration rate by at least 50%, the development of end-stage renal disease, or death from renal or cardiovascular causes, regardless of carbohydrate metabolism status and renal function. Furthermore, treatment with #dapagliflozin** was associated with a reduction in cardiovascular mortality and heart failure hospitalizations, as well as all-cause mortality [305].

The prescription of #empagliflozin** to patients with CKD, in turn, led to an improvement in the combined outcome—the risk of kidney disease progression or death from cardiovascular causes—both in patients with and without diabetes mellitus [306].

Clinical practice guidelines for the management of CKD recommend the inclusion of sodium-glucose cotransporter 2 inhibitors in patients with CKD and type 2 diabetes mellitus to reduce the risk of CKD progression and cardiovascular events [92]. The effect of sodium-glucose cotransporter 2 inhibitors on the course of NAFLD is detailed in Section 3.3.1 "NAFLD Combined with Type 2 Diabetes Mellitus".

Comments: The nephroprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists (#liraglutide, #dulaglutide, #semaglutide**) is mediated through multiple direct and indirect mechanisms, including stimulation of sodium excretion in the proximal tubules, activation of cyclic adenosine monophosphate-dependent protein kinase A (cAMP/PKA), restoration of endothelium-dependent renal vasodilation, normalization of tubuloglomerular feedback (via reduced activity of the sodium-hydrogen exchanger (NHE3)), reduction of renal hypoxia, and others [308]. These drugs are primarily capable of preventing the onset of macroalbuminuria and, to a lesser extent, reducing the decline in the estimated glomerular filtration rate in patients suffering from type 2 diabetes mellitus.

In placebo-controlled trials of liraglutide (LEADER) at 3.8 years of treatment and #semaglutide** (SUSTAIN-6) at 2.1 years of treatment, a significant reduction in the primary composite renal endpoint (development of macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy, or renal death) was achieved in patients with type 2 diabetes mellitus predominantly suffering from CVD [309, 310]. A similar effect in reducing the risk of the composite renal endpoint (renal outcomes as part of microvascular outcomes) was demonstrated by #dulaglutide (the REWIND study with a median follow-up of 5.4 years), primarily through a reduction in the development of macroalbuminuria [311]. However, in terms of their ability to prevent the development of renal complications and reduce the risk of heart failure hospitalizations, these drugs appear to be inferior to sodium-glucose cotransporter 2 inhibitors [312].

Clinical practice guidelines for the management of CKD propose the inclusion of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with CKD and type 2 diabetes mellitus into the treatment regimen to reduce the risk of CKD progression and cardiovascular events [92]. The effect of glucagon-like peptide-1 (GLP-1) receptor agonists on the course of NAFLD is detailed in Section 3.3.1 "NAFLD Combined with Type 2 Diabetes Mellitus".

3.3.5 NAFLD combined with excessive alcohol consumption

The terms NAFLD, NASH, and their criteria proposed in the 1980s implied the strict exclusion of the alcohol factor [313, 314]. Subsequently, it became clear that a combined etiology of fatty liver disease is possible, and excessive alcohol intake by a patient with cardiometabolic risk factors (metabolic dysfunction) potentiates the progression of steatohepatitis. Therefore, in 2023, it was proposed to distinguish a new form—metabolic dysfunction-associated steatotic liver disease combined with increased alcohol consumption (MetALD) [2, 5].

Comments: Alcohol consumption negatively affects the course and prognosis of steatohepatitis in individuals with a metabolic background, and alcohol abuse unfavorably impacts the course of NAFLD. In a large cohort study with a long follow-up period, overall mortality was significantly higher among individuals with NAFLD and heavy alcohol consumption compared to moderate drinkers [317]. In a prospective clinical study, episodic heavy drinking (binge drinking) at least once a month was associated with significant fibrosis progression in NASH [318].

Although earlier individual meta-analyses suggested a protective effect of moderate and small doses of alcohol on NAFLD [319, 320], many studies included in them were methodologically flawed. It has been established that both moderate and low alcohol consumption adversely affects the development of fibrosis in NASH [321, 322]. Furthermore, individuals who consumed alcohol in moderate amounts showed a lesser reduction in steatosis grade and lower chances of NASH resolution compared to complete abstainers [315]. Even moderate alcohol consumption increases the risk of HCC development in patients with NASH [316]. A systematic review of 6 longitudinal observational cohort studies showed that any level of alcohol consumption is associated with worsening liver condition in NAFLD [141].

Comments: Ademetionine** is widely used in the treatment of alcoholic liver disease and has been shown in RCTs to increase survival in patients with alcoholic cirrhosis of Child–Pugh classes A and B [324, 325]. According to experts, ademetionine** can also be used to treat patients with NAFLD who have such a comorbid risk factor as excessive alcohol consumption [323].

3.4 Surgical treatment

Bariatric surgery is considered in patients with NAFLD and BMI > 35 kg/m² when conservative weight loss methods are ineffective in combination with NAFLD.

In addition, patients with cirrhosis due to NASH may undergo liver transplantation, as well as surgical interventions for portal hypertension, but these aspects are discussed in the clinical guidelines "Liver Fibrosis and Cirrhosis", and their management does not have specific features for this etiology of cirrhosis.

Comments: Bariatric surgery can reduce hepatic steatosis, inflammation, and fibrosis, provide sustained weight loss of up to 30%, treat type 2 diabetes mellitus, and reduce all-cause morbidity and mortality. Bariatric treatment is not contraindicated in obese patients with NAFLD or NASH (without verified cirrhosis), although data on its feasibility in patients with liver cirrhosis are limited [1, 174]. According to a meta-analysis including 32 cohort studies and evaluation of 3,093 biopsy specimens, bariatric surgical intervention resulted in a decrease in hepatic inflammatory activity, as well as resolution of steatosis and fibrosis (in 66% and 40% of patients, respectively). Meanwhile, a significantly smaller proportion of patients (12%) experienced worsening of histological features of NAFLD following bariatric surgery [328]. Another meta-analysis observed a reduction in steatosis in 88% and fibrosis in 30% of patients [329]. The most recent meta-analysis, encompassing 37 clinical studies, demonstrated biopsy-proven reduction of steatosis in 56% of patients, inflammation in 45%, and fibrosis in 25% of patients after bariatric surgery. Notably, Roux-en-Y gastric bypass exhibits the greatest efficacy in terms of steatosis reduction, whereas sleeve gastrectomy is most effective for fibrosis regression [330].

Indications and the method of bariatric intervention should be determined on an individual basis by a multidisciplinary team including a surgeon.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation measures for patients with NAFLD are absent. Sanatorium-resort treatment in a gastroenterology profile utilizing physiotherapeutic procedures, regular physical activity, outdoor walks, and alcohol cessation may be recommended.

5. Prevention and Dispensary Observation

Preventive measures should encompass the following directions:

– prevention of NAFLD development;

– timely detection of NAFLD and NASH;

– prevention of NAFLD/NASH progression to liver cirrhosis;

– prevention of hepatocellular carcinoma.

Patients with NAFLD should be managed by multidisciplinary specialists depending on the comorbidity profile (gastroenterologists, endocrinologists, cardiologists, dietitians). Medical efforts should be aimed at preventing both NAFLD itself and NAFLD-associated cardiometabolic diseases.

• To prevent the development of NAFLD, it is recommended to implement measures aimed at establishing a healthy lifestyle, correcting dietary habits, engaging in physical activity, and abstaining from alcohol intake [331].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• Patients with cardiometabolic risk factors without a diagnosis of NAFLD are recommended to undergo screening (platelet count, serum ALT, AST, abdominal ultrasound, FIB-4 calculation) for the timely detection of NAFLD every 3–5 years [332].

LoR CGoE 5Level of Recommendation C (Grade of Evidence 5).

Comments: The diagnosis of NAFLD implies the presence of cardiometabolic risk factors underpinned by metabolic dysfunction. Accordingly, patients with any of its manifestations (obesity, dyslipidemia, type 2 diabetes mellitus, etc.) are considered a risk group for developing NAFLD. In the majority of patients, NAFLD is asymptomatic or accompanied by non-specific symptoms, which frequently causes the disease to remain unrecognized. The optimal frequency of dispensary observation has not been established, but according to European experts, patients with metabolic risk factors without signs of NAFLD should be monitored every 3–5 years [332].

Comments: According to a meta-analysis of clinical studies involving paired liver biopsies, 1/3 of patients with NAFLD experience fibrosis progression. The progression from stage F0 to F1 occurs on average within 14.3 years in baseline simple steatosis and within 7.1 years in NASH [4]. The optimal frequency of dispensary follow-up has not been established, but according to European experts, patients with NAFLD without laboratory or instrumental signs of a progressive course should be monitored every 2 years [332].

Comments: Type 2 diabetes mellitus and other cardiometabolic risk factors contribute to the progressive course of NAFLD and the development of NASH. Approximately 1/4 of patients with established NASH progress to cirrhosis with a risk of developing hepatocellular carcinoma [65]. According to experts, in patients with type 2 diabetes mellitus or multiple cardiometabolic risk factors, the assessment of potential development/progression of fibrosis should be performed every 1–2 years [1].

• Patients with NAFLD are recommended lifestyle modifications (dietary correction, increased physical activity) to prevent NAFLD progression and the development and progression of comorbid conditions [130, 216, 333].

GCR BLEL 1Grade of Recommendation B (Level of Evidence 1).

Comments: Lifestyle modification measures, discussed in detail in Section 3.1 "Non-pharmacological therapy of NAFLD", serve not only as a treatment for NAFLD but also constitute the most effective measure for preventing its onset and progression, while exerting a positive effect on the majority of comorbid conditions [129, 216].

It should be noted that the lack of a definitive consensus on the feasibility of non-pharmacological prevention of NAFLD progression is related to the relatively short duration of randomized trials conducted—1–2 years—whereas convincing data to detect differences in mortality between individuals with NAFLD and the general population can be obtained through follow-up ranging from 8 to 28 years [152]. Nevertheless, lifestyle modification should currently be considered the mainstay method for preventing an unfavorable disease course.

• Patients with NAFLD are recommended pharmacological and non-pharmacological correction of comorbid conditions to prevent an unfavorable course of NAFLD [334].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: NAFLD and many comorbid diseases mutually exacerbate each other. This suggests that the correction of comorbid disorders can have a positive impact on preventing the unfavorable course of NAFLD [334]. There is evidence that certain drugs used in the treatment of NAFLD in combination with diabetes mellitus and dyslipidemia reduce the risk of hepatocellular carcinoma. Thus, according to several meta-analyses, #metformin** is capable of reducing the risk of hepatocellular carcinoma by approximately 50% regardless of the etiology of liver diseases [335–337]. In a meta-analysis of 10 studies involving 4,298 patients with hepatocellular carcinoma out of a total population of 1,459,417 patients, statin use was associated with a significant reduction in the risk of developing this tumor, particularly in Asian populations [338]. When interpreting these findings, it should be taken into account that the majority of these studies were not specifically focused on patients with NAFLD/NASH.

• Patients with NAFLD at the stage of advanced fibrosis (F3) or cirrhosis are recommended to undergo abdominal ultrasound every 6 months for hepatocellular carcinoma screening [339, 340].

GCR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comments: The proportion of hepatocellular carcinoma attributable to NAFLD has been increasing in recent decades, already accounting for 15% of all hepatocellular carcinoma cases with an incidence rate of 0.44 per 1,000 person-years (0.29–0.66) in the NAFLD patient cohort [341–343]. Hepatocellular carcinoma most frequently develops at the stage of advanced fibrosis and liver cirrhosis due to NASH, but it can also occur in simple steatosis [344–346].

It is believed that the risk of developing HCC in NAFLD is highest in patients with diabetes mellitus, older age, and concurrent alcohol consumption, as well as those carrying the PNPLA3 I148M (rs738409) gene polymorphism [340]. Patients at high risk for HCC should be enrolled in surveillance programs [340]. It has been shown that patients with NASH-related cirrhosis who did not participate in HCC screening programs were more likely to present with a more advanced stage of cancer compared to those who participated in screening [347].

Patients with NAFLD-related HCC generally have lower alpha-fetoprotein levels than patients with viral HCC [348].

Patient monitoring should include regular abdominal ultrasound every 6 months [339, 340]. The sensitivity of ultrasound in detecting HCC is 94%, and in detecting early HCC, it is 63% [339].

The necessity of surveillance in patients with NAFLD without cirrhosis has not yet been established [340].

• Patients with NAFLD are recommended to abstain from alcohol and tobacco smoking to reduce the risk of HCC [316, 349].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: In 2/3 of HCC cases, multiple risk factors for its development are identified, with alcohol and smoking serving as established risk factors. An increased risk of HCC has been demonstrated in patients with NAFLD who consume alcohol [316] and smoke [349]. This recommendation is particularly relevant for patients with advanced fibrosis and cirrhosis, as their risk of developing HCC is the highest [344-346].

Comments: First-degree relatives of patients with cirrhosis due to NASH have a 12-fold increased risk of developing advanced liver fibrosis [350].

• Patients with NAFLD in the absence of contraindications are recommended regular coffee consumption to reduce the risk of fibrosis and HCC [351–353].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

Comments: According to several meta-analyses, regular coffee consumption is associated with a reduction in the severity of fibrosis in NAFLD [354–357]. According to other meta-analyses and large epidemiological studies, coffee reduced the risk not only of developing fibrosis in NAFLD but also of the onset of NAFLD itself [351, 352, 358]. Furthermore, coffee consumption has been shown to be associated with a reduced risk of HCC [353].

The protective properties of coffee against NAFLD and HCC are preserved regardless of its caffeine content. Several epidemiological studies conducted in different populations and a dose-response meta-analysis demonstrated a dose-dependent effect of coffee in preventing HCC [359–362]. However, the optimal daily dose of coffee remains unclear.

6. Organization of Medical Care

The majority of patients with NAFLD should be managed and treated on an outpatient basis.

There are no indications for emergency hospitalization in NAFLD.

Indications for elective hospitalization of patients with NAFLD include:

• lack of therapeutic response in an outpatient setting or an atypical disease course;

• need for diagnostic procedures that cannot be performed on an outpatient basis (e.g., liver biopsy);

• need for differential diagnostic procedures to rule out other causes of liver injury that cannot be performed on an outpatient basis (e.g., liver biopsy);

• coexistence of NAFLD with cardiometabolic conditions complicating the disease course, requiring multidisciplinary patient management and/or round-the-clock monitoring.

Criteria for discharge from the hospital: completion of planned diagnostic and differential diagnostic procedures.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Working Group Chairs:

Ivashkin Vladimir Trofimovich – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Propaedeutics of Internal Diseases, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health. No conflict of interest.

Drapkina Oksana Mikhailovna – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Director of the National Medical Research Center for Therapy and Preventive Medicine of the Russian Ministry of Health, President of the Russian Society for the Prevention of Noncommunicable Diseases. No conflict of interest.

Working group secretariat:

Maevskaya Marina Viktorovna - Doctor of Medical Sciences, Professor at I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University). No conflict of interest.

Raykhelson Karina Leonidovna — MD, Professor at the Research and Clinical Educational Center of Gastroenterology and Hepatology of the Medical Institute, Federal State Budgetary Educational Institution of Higher Education "Saint Petersburg State University". No conflict of interest.

Okovity Sergey Vladimirovich — MD, Professor at the Federal State Budgetary Educational Institution of Higher Education "Saint Petersburg State Chemical and Pharmaceutical University" of the Russian Ministry of Health. No conflict of interest.

Zharkova Maria Sergeevna — PhD in Medicine, Head of the Hepatology Department at the Clinic of Propaedeutics of Internal Diseases, Gastroenterology, and Hepatology named after V.Kh. Vasilenko, Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" of the Russian Ministry of Health (Sechenov University). No conflict of interest.

Grechishnikova Vasilisa Romanovna — Postgraduate student, Assistant at the Department of Propaedeutics of Internal Diseases, Gastroenterology, and Hepatology, Institute of Clinical Medicine named after N.V. Sklifosovsky, Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" of the Russian Ministry of Health (Sechenov University). No conflict of interest.

Working Group:

Abdulganieva Diana Ильдаровна — MD, Professor, Head of the Department of Hospital Therapy, Federal State Budgetary Educational Institution of Higher Education "Kazan State Medical University" of the Russian Ministry of Health. No conflict of interest.

Alekseenko Sergey Alekseevich — MD, Professor, Federal State Budgetary Educational Institution of Higher Education "Far Eastern State Medical University" of the Russian Ministry of Health (FESMU). No conflict of interest.

Ardatskaya Maria Dmitrievna — MD, Professor, Federal State Budgetary Institution of Additional Professional Education "Central State Medical Academy" of the Presidential Administration of the Russian Federation. No conflict of interest.

Bakulin Igor Gennadievich — MD, Professor, Head of the Department of Propaedeutics of Internal Diseases, Gastroenterology, and Dietetics named after S.M. Ryss, Federal State Budgetary Educational Institution of Higher Education "North-Western State Medical University named after I.I. Mechnikov" of the Russian Ministry of Health. No conflict of interest.

Bakulina Natalia Valerievna — MD, Professor, Vice-Rector for Research and Innovation, Head of the Department of Internal Diseases, Clinical Pharmacology, and Nephrology, North-Western State Medical University named after I.I. Mechnikov. No conflict of interest.

Bogomolov Pavel Olegovich — PhD in Medicine, Associate Professor at the Department of Propaedeutics of Internal Diseases and Gastroenterology, Federal State Budgetary Educational Institution of Higher Education "A.I. Evdokimov Moscow State University of Medicine and Dentistry", Head of Department and Leading Researcher at the Hepatology Department, State Budgetary Healthcare Institution of the Moscow Region "Moscow Regional Research Clinical Institute named after M.F. Vladimirsky". No conflict of interest.

Breder Valery Vladimirovich — MD, Head of the Department of Drug Therapy, Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Russian Ministry of Health. No conflict of interest.

Vinnitskaya Elena Vladimirovna — MD, Head of the Hepatology Department, State Budgetary Healthcare Institution of the Moscow City Health Department "A.S. Loginov Moscow Clinical Scientific and Practical Center of the Moscow City Health Department". No conflict of interest.

Geyvandova Natalia Ioganovna — MD, Professor, Federal State Budgetary Educational Institution of Higher Education "Stavropol State Medical University" of the Russian Ministry of Health. No conflict of interest.

Golovanova Elena Vladimirovna — MD, Professor at the Department of Therapy and Preventive Medicine, Federal State Budgetary Educational Institution of Higher Education "Russian University of Medicine" of the Russian Ministry of Health. No conflict of interest.

Grinevich Vladimir Borisovich — MD, Professor, Honored Doctor of the Russian Federation, Head of the 2nd Department (Therapy for Advanced Medical Training), Federal State Budgetary Educational Institution of Military Higher Education "S.M. Kirov Military Medical Academy" of the Ministry of Defense of the Russian Federation. No conflict of interest.

Doshchitsin Vladimir Leonidovich — MD, Professor, Pirogov Russian National Research Medical University of the Russian Ministry of Health. No conflict of interest.

Dudinskaya Ekaterina Nailievna — MD, Head of the Laboratory of Age-Related Metabolic and Endocrine Disorders, Structural Unit "Russian Gerontology Clinical Research Center", Federal State Autonomous Educational Institution of Higher Education "Pirogov Russian National Research Medical University" of the Russian Ministry of Health, Professor at the Department of Aging-Related Diseases, Institute of Continuing Education and Professional Development, Faculty of Additional Professional Education of Pirogov Russian National Research Medical University of the Russian Ministry of Health. No conflict of interest.

Ershova Ekaterina Vladimirovna — Highest category physician, PhD in Medicine, Leading Researcher at the Department of Therapeutic Endocrinology, Federal State Budgetary Institution "National Medical Research Center for Endocrinology" of the Russian Ministry of Health. No conflict of interest.

Kodzoeva Khava Bagaudinovna — General practitioner at the Therapeutic Department, Federal State Budgetary Institution "National Medical Research Center of Transplantology and Artificial Organs named after Academician V.I. Shumakov" of the Russian Ministry of Health. No conflict of interest.

Kozlova Irina Vadimovna — MD, Professor, Federal State Budgetary Educational Institution of Higher Education "Saratov State Medical University named after V.I. Razumovsky" of the Russian Ministry of Health. No conflict of interest.

Komshilova Ksenia Andreevna — PhD in Medicine, Endocrinologist at the Department of Thyroid, Adrenal, and Obesity Disorders Therapy, Department of Therapeutic Endocrinology, Federal State Budgetary Institution "National Medical Research Center for Endocrinology" of the Russian Ministry of Health. No conflict of interest.

Konev Yury Vladimirovich — MD, Professor at the Department of Outpatient Therapy, Federal State Budgetary Educational Institution of Higher Education "A.I. Evdokimov Moscow State University of Medicine and Dentistry" of the Russian Ministry of Health. No conflict of interest.

Korochanskaya Natalia Vsevolodovna — MD, Professor, State Budgetary Educational Institution of Higher Professional Education "Kuban State Medical University" of the Russian Ministry of Health. No conflict of interest.

Kotovskaya Yulia Viktorovna — MD, Professor, Deputy Director for Research, Structural Unit "Russian Gerontology Clinical Research Center", Federal State Autonomous Educational Institution of Higher Education "Pirogov Russian National Research Medical University" of the Russian Ministry of Health. No conflict of interest.

Kravchuk Yury Alekseevich — MD, Professor, Federal State Budgetary Educational Institution of Military Higher Education "S.M. Kirov Military Medical Academy" of the Ministry of Defense of the Russian Federation. No conflict of interest.

Loranskaya Irina Dmitrievna — MD, Professor, Dean of the Faculty of Therapy and Head of the Department of Gastroenterology, Federal State Budgetary Institution of Additional Professional Education "Russian Medical Academy of Continuous Professional Education" of the Russian Ministry of Health. No conflict of interest.

Maev Igor Veniaminovich — Academician of the RAS, MD, Professor, Federal State Budgetary Educational Institution of Higher Education "Russian University of Medicine" of the Russian Ministry of Health. No conflict of interest.

Martynov Anatoly Ivanovich — Academician of the RAS, MD, Professor at the Department of Hospital Therapy No. 1, Faculty of General Medicine, Federal State Budgetary Educational Institution of Higher Education "Russian University of Medicine" of the Russian Ministry of Health, President of the Russian Scientific Medical Society of Internal Medicine (RSMSIM). No conflict of interest.

Mekhtiev Sabir Nasredinovich — MD, Professor, Federal State Budgetary Educational Institution of Higher Education "First Pavlov State Medical University of St. Petersburg" of the Russian Ministry of Health. No conflict of interest.

Mishina Ekaterina Evgenievna — PhD in Medicine, Researcher, Endocrinologist, National Medical Research Center for Endocrinology of the Russian Ministry of Health. No conflict of interest.

Nadinskaya Maria Yurievna — PhD in Medicine, Associate Professor at the Department of Propaedeutics of Internal Diseases, Gastroenterology, and Hepatology, Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" of the Russian Ministry of Health (Sechenov University). No conflict of interest.

Nikitin Igor Gennadievich — MD, Professor, Head of the Department of Hospital Therapy No. 2, Faculty of General Medicine, Federal Autonomous State Institution "National Medical Research Center 'Medical and Rehabilitation Center'" of the Russian Ministry of Health; Federal Autonomous State Educational Institution of Higher Education "Pirogov Russian National Research Medical University" of the Russian Ministry of Health. No conflict of interest.

Marina F. Osipenko – MD, PhD, Professor, Head of the Department of Propaedeutics of Internal Diseases, Novosibirsk State Medical University of the Russian Ministry of Health. No conflict of interest.

Olga D. Ostroumova – MD, PhD, Professor, Head of the Academician M.S. Vovsi Department of Therapy and Polymorbid Pathology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. No conflict of interest.

Chavdar S. Pavlov – MD, PhD, Professor, Head of the Department of Therapy at the Institute of Professional Education, Deputy Director for Research and Organization at the N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Head of the Therapy Clinic at the S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department. No conflict of interest.

Nana V. Pogosova – MD, PhD, Professor, Deputy General Director for Research, Analysis and Preventive Cardiology, National Medical Research Center for Cardiology named after Academician E.I. Chazov of the Russian Ministry of Health. President of the National Society of Preventive Cardiology. No conflict of interest.

Valery G. Radchenko – MD, PhD, Professor, Honored Worker of Higher Education of the Russian Federation, Honored Doctor of the Russian Federation, Professor at the 2nd Department (Therapy for Advanced Medical Training), S.M. Kirov Military Medical Academy of the Russian Ministry of Defense. No conflict of interest.

Grigory E. Roitberg – Academician of the Russian Academy of Sciences, MD, PhD, Professor, N.I. Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation. No conflict of interest.

Rafik G. Saifutdinov – MD, PhD, Professor, Kazan State Medical Academy – branch of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health. No conflict of interest.

Alexey A. Samsonov – MD, PhD, Professor at the Department of Propaedeutics of Internal Diseases and Gastroenterology, Faculty of General Medicine, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Ministry of Health of the Russian Federation. No conflict of interest.

Pavel V. Seliverstov – Candidate of Medical Sciences, Associate Professor, S.M. Kirov Military Medical Academy of the Russian Ministry of Defense. No conflict of interest.

Stanislav I. Sitkin – Candidate of Medical Sciences, Associate Professor at the S.M. Ryss Department of Propaedeutics of Internal Diseases, Gastroenterology and Dietetics, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Head of the Research Laboratory of Epigenetics and Metagenomics at the Institute of Perinatology and Pediatrics, V.A. Almazov National Medical Research Centre of the Russian Ministry of Health. No conflict of interest.

Larisa V. Tarasova – MD, PhD, Professor, I.N. Ulyanov Chuvash State University. No conflict of interest.

Aida I. Tarzimanova – MD, PhD, Professor, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University). No conflict of interest.

Olga N. Tkacheva – MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Director of the Russian Gerontology Clinical Research Center, N.I. Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief Geriatrician of the Russian Ministry of Health. No conflict of interest.

Evgeny I. Tkachenko – MD, PhD, Professor, Honored Scientist of the Russian Federation, Honored Doctor of the Russian Federation, Professor, S.M. Kirov Military Medical Academy. No conflict of interest.

Ekaterina A. Troshina – MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Deputy Director of the National Medical Research Center for Endocrinology of the Russian Ministry of Health – Director of the Institute of Clinical Endocrinology. No conflict of interest.

Svetlana V. Turkina – MD, PhD, Professor, Volgograd State Medical University of the Ministry of Health of the Russian Federation. No conflict of interest.

Yury P. Uspenskiy – MD, PhD, Professor, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation. No conflict of interest.

Yulia A. Fominykh – MD, PhD, Associate Professor, V.A. Almazov National Medical Research Centre of the Ministry of Health of the Russian Federation, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation. No conflict of interest.

Olga V. Khlynova – MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Hospital Therapy and Cardiology, Academician E.A. Vagner Perm State Medical University of the Russian Ministry of Health. No conflict of interest.

Yulia V. Tsyganova – Candidate of Medical Sciences, Associate Professor, I.N. Ulyanov Chuvash State University. No conflict of interest.

Minara Sh. Shamkhalova – MD, PhD, Professor, National Medical Research Center for Endocrinology of the Russian Ministry of Health. No conflict of interest.

Olga O. Sharkhun – MD, PhD, Professor, N.I. Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation. No conflict of interest.

Marina V. Shestakova – MD, PhD, Professor, Academician of the Russian Academy of Sciences, National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation.

Appendix A2. Methodology for Developing Clinical Guidelines

These clinical guidelines aim to provide practitioners with modern concepts of the etiology and pathogenesis of NAFLD, and to introduce currently used algorithms for diagnosis, prognostic assessment, and treatment.

Target audience of these clinical guidelines:

1) gastroenterologists;

2) general practitioners (family physicians);

3) internists;

4) cardiologists;

5) endocrinologists;

6) oncologists.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of evidence (LoE) indicating the classification used for levels of evidence

Table 3. Levels of recommendation persuasiveness with indication of the classification used (LRP)

Procedure for updating clinical guidelines

The guideline updating mechanism provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 906n dated November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Population in the Profile 'Gastroenterology'."

2. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

3. Order of the Ministry of Health of the Russian Federation No. 772n dated November 9, 2012, "On Approval of the Standard of Medical Care for Other Liver Diseases."

Appendix B. Physician Action Algorithms

Differential diagnosis algorithm for causes of fatty liver disease

* a) BMI > 25 kg/m2 (Caucasians) or > 23 kg/m2 (Asians) or waist circumference > 94 cm in men and > 80 cm in women; b) fasting glucose > 5.6 mmol/L, or postprandial glucose > 7.8 mmol/L, or HbA1c > 5.7%, or already diagnosed type 2 diabetes, or ongoing treatment for type 2 diabetes; c) blood pressure > 130/85 mmHg or pharmacotherapy for already diagnosed hypertension; d) plasma triglycerides ≥ 1.70 mmol/L or lipid-lowering treatment; e) plasma HDL-C < 1.0 mmol/L in men and < 1.3 mmol/L in women or lipid-lowering treatment. LAL D – lysosomal acid lipase deficiency.

Follow-up algorithm for patients with NAFLD

* For the purpose of early diagnosis of HCC.

Appendix C. Patient Information

The key to success in treating NAFLD:

• healthy diet;

• physical activity.

❖ Reduce portion sizes; eat frequently if possible, but in small portions.

❖ Exclude foods rich in simple carbohydrates (sweets, flour products) from your regular diet and try to consume them occasionally and in small amounts.

❖ Try to eat vegetables and fruits several times a day.

❖ Replace sweet and carbonated beverages with water or unsweetened drinks.

❖ Eat high-fiber foods, including whole grains.

❖ Avoid saturated fats, use extra virgin olive oil as the main added source of fat in meals.

❖ Eat fish 2–3 times a week.

❖ Avoid processed foods and fast food.

❖ Read food labels to find hidden fat, sodium, and sugar.

❖ Try to engage in some form of physical activity for at least 60 minutes a day. This does not have to be all at once. Walk more, exercise, and take the stairs whenever possible.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. NAS (NAFLD activity score)

(Bedossa P. Current histological classification of NAFLD: strength and limitations. Hepatol Int. 2013;7(Suppl. 2):765–770. https://doi.org/10.1007/s12072-013-9446-z).

Russian name: NAFLD Activity Score.

Source: CRN (Clinical Research Network) morphologist expert consensus (2005).

Purpose: for semi-quantitative assessment of the severity and stage of NAFLD.

Content (template): The score evaluates the degree of morphological changes in points (from 0 to 8): the severity of hepatic steatosis, intralobular (lobular) inflammation, hepatocyte ballooning degeneration, and fibrosis stage.

* Presence of inflammatory infiltrate cell clusters at 20x magnification.

Key (interpretation):

• NAS 0–2 – NASH diagnosis is unlikely;

• NAS 3–4 – "grey zone", NASH may be present in the patient;

• NAS ≥ 5 – probable diagnosis of NASH.

Appendix G2. SAF score

(Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014;60(2):565–575. https://doi.org/10.1002/hep.2717310.1002/hep.27173).

Russian name: Scale for semi-quantitative assessment of NAFLD severity.

Source: FLIP Pathology Consortium (2014).

Purpose: for semi-quantitative assessment of NAFLD severity.

Content (template): The scale includes histological features of NAFLD such as severity of steatosis (S – steatosis), ballooning degeneration and lobular inflammation (A – activity), and liver fibrosis stage (F – fibrosis).

* The presence of (sub)total hepatic steatosis in young patients, especially without signs of metabolic syndrome, requires assessing lysosomal acid lipase activity to rule out cholesterol ester storage disease / Wolman disease or screening the patient for Wilson disease. A rarer cause may be carriage of recessive mutations in POLG (DNA Polymerase Subunit Gamma), DGUOK (Deoxyguanosine Kinase), or MPV17 (Mitochondrial Inner Membrane Protein MPV17), characteristic of mitochondrial diseases.

Key (interpretation): the evaluation result is recorded as an index such as S1A2F3, S2A1F1, etc.

Appendix G3. Fibrosis-4 index, FIB-4

(Sterling RK, Lissen E, Clumeck N, et. al. Development of a simple noninvasive index to predict significant fibrosis patients with HIV/HCV co-infection. Hepatology 2006;43:1317-1325).

Russian name: Fibrosis-4 index.

Purpose: non-invasive assessment of potential fibrosis in NAFLD.

Content (template):

FIB-4 = age ([years] x AST [IU/L]) / ((platelets [10(9)/L]) x (ALT [IU/L])(1/2)).

Key (interpretation):

• >1.3 – risk of significant fibrosis;

• >3.25 – high risk of significant fibrosis.

Appendix G4. NAFLD Fibrosis Score, NFS

(Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54)

Russian name: NAFLD fibrosis score.

Purpose: non-invasive assessment of potential fibrosis in NAFLD.

Content (template):

NFS = −1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × (impaired glucose tolerance or diabetes mellitus [yes=1, no=0]) + 0.99 × (AST/ALT ratio) − 0.013 × platelets (×10⁹/L) − 0.66 × albumin (g/dL).

Key (interpretation):

• <1.455 – low risk of significant fibrosis;

• 1.455–0.67 – indeterminate result;

• >1.455 – high risk of significant fibrosis.