Phenotypes of non-alcoholic fatty liver disease in people with normal and increased body mass: issues of epidemiology and etiology, clinical and pathogenetic features and diagnostic approaches. Literature review

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Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, affecting 20–40 % of the population, continuing to grow steadily, and becoming the most common indication for liver transplantation [1; 2]. NAFLD is most commonly reported in individuals who are overweight or obese, which increases the risk of developing hepatic steatosis by more than 3.5 times. Obesity is a major risk factor for NAFLD, the prevalence of which correlates directly with an increase in body mass index BMI [3; 4].

However, in some people who are overweight or even obese, the intrahepatic fat content remains normal, while others of normal weight develop NAFLD even in the absence of metabolic risk factors. Therefore, recent terminology has begun to distinguish a specific NAFLD phenotype in individuals with normal body weight (NBW) who have a body mass index (BMI) of less than 25 kg/m² (less than 23 kg/m² for Asians) [5–9]. The pathophysiology of this phenotype has not been sufficiently studied. Some characteristics of NAFLD phenotypes are similar in obese and normal-weight individuals, but not all normal-weight individuals with NAFLD have metabolic disorders that predispose them to liver dysfunction. There is an opinion that in this case, the influence of factors such as diet, physical activity, constitutional and genetic characteristics should be taken into account [7; 9; 10]. Patients with NAFLD and NBW, despite their more favorable metabolic profile, are no less at risk of disease progression than obese individuals, which requires a more detailed study of this NAFLD phenotype, the development of early screening algorithms, and treatment strategies depending on the underlying cause of the disease.

The aim of the study is to summarize literature and our own data on the prevalence of NAFLD phenotypes in individuals with normal and overweight body mass, risk factors, clinical and pathogenetic features, and diagnostic approaches.

NAFLD Phenotype in Individuals with NBW

As mentioned above, NAFLD is diagnosed in individuals with NBW when this liver pathology is present with a BMI of less than 25 kg/m² (for non-Asian races) and less than 23 kg/m² (for Asian races). The lower BMI threshold for Asians is due to the higher prevalence of NAFLD, visceral obesity, and metabolic complications in this ethnic group, while the prevalence of general obesity is lower [11]. This phenotype is characterized by the presence of visceral obesity, sarcopenia, cardiometabolic risks (hypertension, dyslipidemia, and hyperglycemia) and is defined as “metabolically obese people with normal weight” (metabolically obese, normal- weight, MONW) [12; 13].

Prevalence of NAFLD in Individuals with Normal and Overweight Body Mass

An analysis of NAFLD incidence over a 10-year period, from 2005 to 2016, showed a significant increase from 25.5 % to 37.8 %, which is due to rising rates of obesity and type 2 diabetes mellitus (DM) worldwide. According to some data, by 2030, there is expected to be a 21 % increase in cases of fatty liver disease and a 63 % increase in cases of steatohepatitis [14]. NAFLD varies in prevalence and severity depending on ethnicity, region, and gender. In the US, fatty liver disease occurs in 20–46 % of the population, according to various sources, in Italy it is registered in 16 % of people, and in Southeast Asia the prevalence of NAFLD ranges from 21 to 27.3 % [15], and in Russia, the prevalence of NAFLD among polyclinic patients is 37.3 %. The variability of NAFLD is also associated with ethnic characteristics (45 % in Latin Americans, 33 % in European, and 24 % in equatorial races) [14]. Gender and age factors also influence the prevalence and risk of NAFLD progression. Many studies show that men have a higher risk of developing NAFLD—up to 50 % in the population [16]. However, over the past 10 years, there has been a trend toward an increase in the prevalence of NAFLD among women, especially in postmenopausal women, which is primarily associated with overweight and obesity, including visceral obesity, which is recorded in more than 40 % of women over 45 and more than 50 % of women over 55, as well as metabolic comorbidity [17; 18]. According to our data, 46 % of postmenopausal women with NAFLD and increased body weight have metabolic risk factors (33 % of patients had two metabolic components, 13 % had three) [19].

Data on the prevalence of NAFLD in individuals with NBW in the population are highly heterogeneous, ranging from 5 to 34 %, which is associated with geographical factors, the method of determining NAFLD, and the design and sample size of studies [10]. The first population-based epidemiological studies of NAFLD in non-obese individuals were initiated in 2004 on the Asian continent. In one of the first studies, the prevalence of NAFLD among the Asian population not suffering from obesity was more than 23 %. At the same time, they had the same risk factors as individuals with excess weight, including male gender, older age, and metabolic comorbidity [20; 21]. In China, in a study involving 911 people, the prevalence of NAFLD among people who were not obese was 19.3 % [22], and in Japan it was 15.2 % [23]. The prevalence of NAFLD among Belgians who were not obese or diabetic and who underwent liver biopsy due to chronic liver disease was 2.8 % [24]. The highest prevalence rates of NAFLD (over 30 %) and increased insulin resistance in non-smoking men of Asian-Indian origin were observed in India [25]. A comprehensive meta-analysis using data from 84 studies showed that among patients with NAFLD, 19.2 % of participants were thin [26]. However, in another study in the general population, including all people regardless of NAFLD status, only 5.1 % were diagnosed with NAFLD at normal BMI. According to 19 studies, NAFLD was diagnosed in 10.6 % of 49,503 people of normal weight. Overall, the prevalence of NAFLD in people who are not obese was higher in European countries and lower in Asian countries. Data from the Global Registry, which includes information from 18 countries, showed that approximately 8 % of patients with NAFLD had a normal BMI and fewer signs of metabolic comorbidity [27].

In another large nationwide European study involving more than 200,000 people, 16.3 % with NAFLD had a normal BMI, 41 % were overweight, and 42.7 % were obese [28]. In Russia, data on the prevalence of NAFLD among people who are not obese are very scarce. In the Volgograd region, among patients with NAFLD, the proportion of individuals with NBW was 16.2 %, with overweight and obesity – 26.4 % and 57.4 %, respectively [29], which is comparable to European data.

Etiopathogenetic Characteristics of NAFLD Phenotypes

The variability in the course and outcomes of NAFLD is associated with factors such as age, gender, ecology and environmental factors, ethnicity, dietary characteristics, hormonal influences, genetic predisposition, metabolic diseases, and comorbidity, leading to the formation of different phenotypes of this disease [30].

In both sexes, the progression of NAFLD is associated with metabolic components such as obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension, as well as age.

NAFLD is associated with frequent consumption of sucrose and fructose [31], which is confirmed by experimental studies [32].

An important role in the NAFLD phenotype with increased body weight (IBW) is played by dysfunction and lipotoxicity of adipose tissue, which produces free fatty acids during lipolysis, inflammation mediators, and adipokines, leading to the development of insulin resistance, inflammation, oxidative stress, mitochondrial and endothelial dysfunction, as well as the accumulation of lipids in non-adipose tissues, including the liver, with the formation of NAFLD [33–35]. Moreover, increased obesity severity is characterized by an increase in structural and functional disorders in the liver [36]. Adipose tissue, especially visceral adipose tissue, produces pro-inflammatory cytokines and vascular endothelial growth factors, which activate local inflammation in hepatocytes, dysfunction of the endothelium of hepatic hemocapillaries, and lead to the progression of NAFLD [37–39]. The course of NAFLD in women with IBW may be determined by menopausal and estrogen status [40; 41]. Most of the variability—from 25 to 75 % of NAFLD—in the population is also associated with genetic factors. Several genes have been identified that influence lipid metabolism in the liver: PNPLA3, TM6SF2, MBOAT7, HSD17B1 and GCKR [42; 43]. There is evidence that polymorphism of the VEGFA gene and a number of cytokines may influence the development of liver diseases [44–47].

Despite similar pathological changes in the liver, the factors contributing to the development and progression of NAFLD in individuals with NBW have not yet been sufficiently studied compared to those in whom NAFLD develops against a background of IBW.

However, recent literature has suggested a number of factors that are likely to influence the risk of developing and progressing NAFLD even in the absence of excess weight: diet, environmental factors, genetic predisposition, endocrine and metabolic dysfunction. In addition to factors such as high fructose consumption, there is currently discussion about the link between NAFLD and individuals with NBW who have a deficiency of choline, an important nutrient for human health [48]. Studies show that a three-week deficiency in healthy male volunteers increases liver transaminase activity, and prolonged choline deficiency causes significant liver dysfunction in postmenopausal women and men [48; 49]. Since choline is found in higher concentrations in animal products, vegetarians and vegans may be at greater risk of deficiency and, consequently, at higher risk of NAFLD due to insufficient intake [50].

Other environmental factors that may influence NAFLD include alcohol consumption and smoking.

In people with NAFLD, consuming more than seven units of alcohol per week significantly increased the likelihood of death from cardiovascular disease and was associated with significantly higher rates of complications generally, as well as cardiovascular and cancer complications [51]. The role of moderate alcohol consumption and NAFLD in thin people has not yet been studied. Cigarette smoking is associated with the onset of NAFLD, progression to fibrosis, and an increased risk of developing severe liver disease [52].

The main genetic risk factor for NAFLD known to date is a single nucleotide variant leading to the substitution of I148M (rs738409) in the patatin-like phospholipase C-containing protein 3 gene (PNPLA3) [53]. In addition to PNPLA3, variants of MBOAT7 (membrane-associated O-acyl transferase domain 7) and TM6SF2 (transmembrane superfamily antigen 2 are associated with NAFLD 6) [54]. Most studies of genetic associations have been conducted in people with classic NAFLD associated with obesity, and there is little data on people of normal weight with fatty liver disease. In a study involving 904 Japanese people, in whom the prevalence of NAFLD was 12.4 %; 41.4 % and 59.1 % in the normal weight, overweight, and obese groups, respectively, the PNPLA3 rs738409 (GG) risk genotype increased the risk of NAFLD in people with NBW by more than two times compared to overweight and obese participants [55]. When stratified by IBW, no differences in risk were found for MBOAT7 or TM6SF2 alleles associated with NAFLD. In a study involving 187 Austrians, Feldman et al. [56] found a higher frequency of PNPLA3 risk alleles in thin individuals with NAFLD compared to a control group of thin individuals—that is, a frequency comparable to that in patients with NAFLD and obesity. The genetic risk rs738409 was also associated with NAFLD in thin people in the Sri Lankan population [57] and in Japanese patients without obesity [58]. Other research groups did not find statistically significant differences in NAFLD risk alleles in PNPLA3 and TM6SF2 between groups with different weights. Variants in genes involved in choline biosynthesis, namely cholinesterase A, mitigated the effects of a low-choline diet, while genetic predisposition consisting of variants in genes involved in choline metabolism and 1-carbon metabolism was associated with the severity of hepatic steatosis [59].

There is a hypothesis that NAFLD in people with NBW may be a type of ectopic fat deposition similar to lipodystrophy. Lipodystrophy is a group of diverse rare genetic disorders characterized by a common phenotype of adipose tissue deficiency without nutrient deficiency or increased metabolism [60]. The inability to store lipids as fat leads to several adverse complications, including NAFLD and liver fibrosis, which can lead to cirrhosis. Pathogenic variants in several genes can cause familial partial lipodystrophy, including peroxisome proliferator-activated receptor gamma (PPARG), lamin A/C (LMNA), perilin 1 (PLIN1), hormone-sensitive lipase (LIPE), DFFA-like effector C inducing cell death (CIDEC), and homolog 2 of the mouse thymoma viral oncogene Akt (AKT2) [61]. Genetic data confirm this mechanism. A polygenic risk index associated with insulin resistance and reduced fat mass in the lower extremities, which are signs of lipodystrophy and linked to NAFLD and an increased risk of liver fibrosis, has been reported [62].

NAFLD can develop against a background of endocrine disorders, often exacerbating metabolic changes associated with hormonal dysfunction. A decrease in estrogen production leads to a reduction in PEMT expression, which may increase the predisposition to NAFLD in postmenopausal women with chronic choline deficiency [63]. Other potential causes of NAFLD in people with NBW include intestinal dysbacteriosis, parenteral nutrition, malnutrition, and the use of certain steatogenic drugs [10].

The development of NAFLD in patients with NBW can be explained by the functioning of the “intestine-liver” axis. With the development of metabolomics and modern molecular technologies, the role of microbial metabolites and the complex interaction of the microbiota with the host organism in the pathogenesis of liver diseases has been identified. There is a close structural and functional relationship between the liver and the intestine. The liver receives 75 % of its blood supply from the intestine via the portal vein, so it is constantly exposed to factors caused by metabolic processes in the intestine, which are largely determined by the microbiota. When the intestinal barrier is disrupted, the liver is exposed to pathological factors coming from the intestine. In turn, changes in physiological processes in the liver can cause intestinal dysfunction [64]. Liver diseases lead to dysbacteriosis and excessive bacterial growth in the intestine. Accumulating data have demonstrated a complex relationship between the intestinal microbiota and the outcomes of chronic liver diseases [65; 66].

More than ten years ago, systematic analysis of the intestinal microbiota was conducted in fatty liver disease [67]. The link between the microbiota and NAFLD has been found in various population cohorts. It is important to note that specific gut microbiome profiles may influence disease progression in patients with NAFLD [68]. The literature more often contains data on an increase in the Bacteroidetes/Firmicutes ratio in patients with NAFLD [69; 70]. However, in a study by B. Wang et al. [71], patients with NAFLD were found to have an increase in Firmicutes bacteria and a decrease in Bacteroidetes bacteria compared to healthy volunteers. A decrease in the number and metabolic activity of butyrate-producing bacteria Faecalibacterium, Anaerosporobacter, Coprococcus, and Ruminococcus, which have anti-inflammatory activity, has been demonstrated in a number of studies. In the pediatric NAFLD cohort, Zhu et al. observed a significant increase in the Enterobacteriaceae family, accompanied by an increase in blood alcohol concentration, compared to obese and healthy individuals [72]. A Chinese study found that Klebsiella pneumoniae produces ethanol during metabolism, which contributed to the development of NAFLD in patients [73]. K. Wijarnpreecha et al. conducted a meta-analysis that revealed a significant association between NAFLD and small intestinal bacterial overgrowth syndrome (SIBO) (OR 3.82; 95 % CI 1.93–7.59; р <  0.0001) [74]. Other researchers have also demonstrated a link between NAFLD and SIBO [75]. In addition, the possible role of Helicobacter pylori in the pathogenesis of NAFLD is being discussed [76]. Recent studies have shown that H. pylori infection may be an independent risk factor for NAFLD, increasing the severity of NAFLD by impairing liver function, causing inflammatory reactions, and affecting the processes of glucose metabolism and lipid metabolism [77]. Possible mechanisms of microbiota involvement in the pathogenesis of NAFLD are presented in Table.

 

Possible mechanisms of microbiome involvement in the pathogenesis of NAFLD

No.		The role of microbiota	Explanation of involvement in the pathogenesis of NAFLD
1		Expression of hunger-induced fat factor (Fiaf)	It has now been proven that normal intestinal microbiota contributes to a reduction in the expression of Fiaf, which is a suppressor of lipoprotein lipase—a key regulator of the release of fatty acids from triglyceride-rich lipoproteins in adipose tissue, skeletal muscle, and cardiac muscle [78]
2		Regulation of intestinal epithelial barrier permeability associated with the level of lipopolysaccharide-binding protein (LPS-protein) and lipopolysaccharides (LPS)	The content of LPS, which originate from Gram-negative bacteria, is increased in patients with NAFLD. LPS activate Kupffer cells and stellate cells by acting on their receptors, TLR4. In addition, LPS activates the NLRP3 inflammasome, an inducer of inflammation. As a result, the production of pro-inflammatory cytokines in the liver increases, i.e., LPS is an inducer of necrotic inflammatory lesions and the development of fibrosis in patients with NAFLD [79]
3		Activation of innate immune mechanism	It has been established that the intestinal microbiota releases molecularly associated components that are biologically Toll-like receptor (TLR) ligands [80]. It has now been proven that TLR types 2, 4, and 9 are involved in the pathogenesis of NAFLD in humans [81]. The intestinal microbiota and the endotoxins it secretes participate in the mechanism of insulin resistance development through the transmission of TLR signals, in particular, through TLR4 on the surface of monocytes, mast cells, B cells, and intestinal epithelium with the CD14 system [82]. During the binding of LPS to the LPS-protein-TRL4 complex on Kupffer cells, an intracellular inflammatory cascade is triggered, activating the nuclear transcription factor kappa B (NF-κB) and the associated production of proinflammatory cytokines [83; 84]. TLR4 is also expressed on the surface of stellate cells, which can be activated by LPS, produce extracellular matrix components, and trigger fibrogenesis in the liver, which progresses against the background of existing endotoxemia [85]
4		Deconjugation of bile acids (BA)	Microbiota deconjugates primary bile acids and alters the ratio of primary to secondary bile acids. In turn, deconjugated bile acids stimulate nuclear farnesoid X receptors (FXR), triggering the process of triglyceride deposition in the liver [86]. In the intestine, FXR binds bile acids, leading to the activation of the target gene fibroblast growth factor 15 (FGF15). In turn, FGF15 inhibits the expression of cholesterol 7-hydroxylase in the liver (Cyp7a1), maintaining the enzyme ratio in BA biosynthesis [87]. Secondary BAs activate FXR more strongly than primary BAs [88]. These receptors are mostly expressed in the liver and kidneys, ileum, pancreas, and adrenal glands [89]. Receptors play an important role in the metabolism of BAs, glucose, and lipids [90]. In the liver, BAs bind directly to FXR, forming a complex that improves glucose and cholesterol metabolism in liver tissue, reducing fat accumulation in hepatocytes [64]. It should be assumed that when dysbiosis occurs, the deconjugation of primary bile acids decreases. And since secondary bile acids activate FXR more strongly, there will be a decrease in the suppression of inflammatory genes. At a certain stage, adaptive mechanisms in patients with NAFLD break down, leading to a decrease in FXR expression, a decrease in bile acid production and their entry into the intestine, as a result of which it becomes impossible to suppress bacterial growth and uncontrolled reproduction of pathogenic intestinal bacteria occurs. The pathogenicity of Gram-positive bacteria is ensured by peptidoglycans and lipoteichoic acids [91]
5		Generation of short-chain fatty acids (SCFA)	It is known that intestinal bacteria, when in a stable healthy state, produce short-chain fatty acids (SCFAs) after fermenting dietary fiber, the main ones being acetic, propionic, and butyric acids [92]. This is the main class of bacterial metabolites. The role of SCFAs was studied by C.M. Sawicki (2017) and A. Koh (2016) and consisted in providing an energy substrate for colonocytes, balancing the integrity of the intestinal barrier, controlling inflammation in the intestine, and promoting a feeling of satiety. Entering the liver through the portal vein, these metabolites are used in gluconeogenesis and lipogenesis as an energy substrate. SCFAs from the colon reaches the systemic bloodstream and other tissues, leading to the activation of brown adipose tissue, regulation of liver mitochondrial function, insulin secretion by pancreatic β-cells, and stimulation of whole-body energy homeostasis. However, SCFAs are used for TG synthesis in the liver, an excess of which, in turn, can lead to steatosis. In addition, excessive accumulation of SCFA leads to inhibition of adenosine monophosphate-activated protein kinase (AMPK) in the liver, increasing the accumulation of liver FFA due to a decrease in β-oxidation [93]. In an attempt to explain the pathogenetic link between NAFLD and SCFA, it has been established that the latter bind to receptors directly connected to G protein—GPR41 (FFAR3), GPR43 (FFAR2), and GPR109A, which are located on the surface of intestinal epithelial cells, adipocytes, hepatocytes, and pancreatic beta cells. The intestinal microbiota is a component necessary for the normal functioning of GPR43 receptors, most likely due to the synthesis of SCFA by bacteria, which are GPR43 agonists [94]. Butyrate has been shown to activate hepatic expression of glucagon-like peptide-1 receptors (GLP-1R) by inhibiting histone deacetylase 2 (HDAC2), which improves hepatic sensitivity to GLP-1 and prevents the progression of NAFLD [95]
6		Participation in choline metabolism	Choline is a hepatoprotective and lipotropic agent which, in combination with lecithin, promotes the transport and metabolism of fats in the liver. Its deficiency is one of the causes of NAFLD. It can be caused not only by insufficient intake with food, but also by high levels of bacteria that utilize choline, mainly represented by Enterobacteriaceae and especially Escherichia. Firmicutes and Proteobacteria, which metabolize choline into trimethylamine (TMA), increase in dysbiosis, which can lead to a decrease in the availability of dietary choline. Trimethylamine N-oxide (TMAO), derived from TMA, is associated with liver damage [96]
7		Production of endogenous ethanol	Intestinal dysbiosis is associated with an increase in the number of ethanol-producing bacteria, mainly Escherichia and Lactobacillus species and some Ruminococcaceae species. Recent studies have shown a positive correlation between Escherichia/Shigella, Ruminococcus, and the Enterobacteriaceae family and severe fibrosis, which may be due to increased microbial ethanol production [97]
8		Catabolism and recycling of amino acids	Bacteria in the intestinal microbiota play an important role in the catabolism and recycling of amino acids. The most common bacteria that ferment amino acids are members of the Clostridia, Peptostreptococci, and Enterobacteria species. It is known that the microbiota metabolizes aromatic amino acid tryptophan to form kynurenine, serotonin, and indole derivatives (indole-3-acetic acid (I3A), indolepropionic acid (IPA), indole-3-lactic acid, indole-3-carboxylic acid, and tryptamine).  The study by C. Caussy and R. Loomba showed that the content of 3-(4-hydroxyphenyl) lactate, a product of tyrosine metabolism, increases in patients with steatosis and liver fibrosis. Branched-chain amino acids include leucine, isoleucine, and valine. These amino acids are formed by proteolytic fermentation in the large intestine by Clostridium, Fusobacterium, Bacteroides, Actinomyces, Propionibacterium, and Peptostreptococcus bacteria. As steatosis progressed to steatohepatitis, patients showed elevated levels of branched-chain amino acids, leading to chronic activation of mechanistic target of rapamycin kinase (mTOR), which is a critical mediator of protein synthesis, cell proliferation, and insulin sensitivity regulation. This leads to increased insulin secretion and, as a result, to the development of IR, the main risk factor for steatosis [98] amino acid tryptophan to form kynurenine, serotonin, and indole derivatives (indole-3-acetic acid (I3A), indolepropionic acid (IPA), indole-3-lactic acid, indole-3-carboxylic acid, and tryptamine). The study by C. Caussy and R. Loomba showed that the content of 3-(4-hydroxyphenyl) lactate, a product of tyrosine metabolism, increases in patients with steatosis and liver fibrosis. Branched-chain amino acids include leucine, isoleucine, and valine. These amino acids are formed by proteolytic fermentation in the large intestine by Clostridium, Fusobacterium, Bacteroides, Actinomyces, Propionibacterium, and Peptostreptococcus bacteria. As steatosis progressed to steatohepatitis, patients showed elevated levels of branched-chain amino acids, leading to chronic activation of mechanistic target of rapamycin kinase (mTOR), which is a critical mediator of protein synthesis, cell proliferation, and insulin sensitivity regulation. This leads to increased insulin secretion and, as a result, to the development of IR, the main risk factor for steatosis [98]

 

Clinical Characteristics and Prognosis of Different Phenotypes of NAFLD

A number of studies have compared the clinical characteristics of obese and non-obese groups with NAFLD. In general, lean individuals with NAFLD have a more favorable metabolic profile compared to individuals with a higher BMI. However, despite the more favorable metabolic profile, the risk of disease progression to steatohepatitis in individuals with NAFLD at NBW is comparable to the risk observed in patients with NAFLD who are overweight or obese. In one study of patients with NAFLD confirmed by liver biopsy, the severity of inflammation and fibrosis did not differ according to body weight, and the prevalence of NASH in people of normal weight was 50 % (compared to 68.8 % in the group of NAFLD patients who were overweight or obese) [99]. Another study showed that 42 % of patients with NAFLD and NBM had steatohepatitis, of whom 42.3 % had fibrosis scores of 2 or higher [100]. In another study, the indicators of portal inflammation, lobular inflammation, hepatocyte swelling, perisinusoidal and periportal fibrosis were similar in the NAFLD groups with NBW and IBW [101]. On the contrary, a multinational study showed that thin people with NAFLD have significantly less steatosis, lobular inflammation, Balloon dystrophy, and progressive liver fibrosis compared to the overweight group, although 50 % and 10 % of thin people had mild/moderate fibrosis and progressive fibrosis, respectively [102]. The results of meta-analyses are consistent with a more favorable metabolic profile and milder disease progression in thin people with NAFLD.

Data from studies investigating the outcomes and prognosis of NAFLD phenotypes are also highly variable. For example, in a cohort of 1,339 NAFLD patients from Australia, Italy, Spain, and the United Kingdom, who were followed for an average of 7.6 years, 6.2 %, 7.3 % and 1.0 % of thin people developed diabetes, cardiovascular disease, and hepatocellular carcinoma, respectively, with no significant differences in incidence or overall survival between the normal and high BMI groups [102]. In other studies, patients with NAFLD and NBW showed an increased risk of developing severe liver disease compared to patients with higher BMI [103]. A recent study by Zou et al. showed that thin NAFLD patients had the highest all-cause mortality over 15 years (76.3 %) compared to NAFLD patients without obesity (51.7 %), patients with NAFLD and obesity (27.2 %), and people without NAFLD (20.7 %) [104]. These data indicate that, despite lower body fat mass, a more favorable baseline metabolic profile, and lower liver transaminase levels, thin people with NAFLD have the same or higher risk of cardiovascular disease and all-cause mortality associated with NAFLD than people with higher BMI, which is probably due to the pathogenic features of this phenotype.

Criteria for Diagnosing of NAFLD

NAFLD is diagnosed when there is fatty liver disease in the absence of other causes contributing to fat accumulation in the liver (alcoholic origin, drug etiology, viral and hereditary diseases).

In 2024, Russia adopted new diagnostic criteria for NAFLD that take into account cardiometabolic risk factors [105].

Diagnostic criteria for NAFLD:

1. Liver steatosis detected by imaging (ultrasound or other tests) or histologically,

in combination with one or more of the following cardiometabolic risk factors.

2. Cardiometabolic risk factors:
   
   • body mass index > 25 kg/m² (European) or 23 kg/m² (Asian), waist circumference > > 94 cm (for men), 80 cm (for women);
   • fasting glucose > 5.6 mmol/L, or postprandial glucose > 7.8 mmol/L, or HbAlc > > 5.7 %, or type 2 diabetes, or treatment for type 2 diabetes;
   • blood pressure > 130/85 mmHg or antihypertensive medication;
   • TG in plasma > 1.70 mmol/L or lipid-lowering treatment;
   • HDL cholesterol in plasma <  1.0 mmol/L (for men) and <  1.3 mmol/L (for women).

Experts from the American Gastroenterological Association have published recommendations for the management of NAFLD in thin patients, according to which this pathology should be suspected in thin individuals over 40 years of age with a BMI of less than 25 kg/m² (for non-Asian races) or less than 23 kg/m² (for Asian races) with metabolic diseases (diabetes mellitus, dyslipidemia, arterial hypertension), elevated liver enzymes, and liver stenosis. The diagnostic search algorithm in this cohort includes: BMI assessment, routine search for comorbidities, fibrosis staging (NAFLD fibrosis score and Fibrosis-4 score panels, liver imaging using transient elastography or MR elastography), assessment of alcohol consumption, exclusion of other causes of liver damage. A liver biopsy should be performed when the cause of liver damage is unknown or to determine the degree of liver fibrosis [10].

Conclusions

Individuals with NBW often develop NAFLD despite having a healthier metabolic phenotype than those with classic NAFLD associated with IBW obesity. When assessing the risk of NAFLD in people of normal weight, it is important to consider menopausal status, genetic factors, ethnicity, dietary characteristics (consumption of sugar, refined carbohydrates, and saturated fats / cholesterol), choline deficiency, and alcohol consumption and smoking habits.

It is also necessary to develop screening algorithms that are less dependent on BMI and liver transaminase levels, introduce more accurate treatment strategies based on the pathogenesis of the disease, and include people with NBW in clinical studies related to NAFLD to identify factors that modulate the risk of liver steatosis, including in the absence of clinically significant metabolic dysfunction.

About the authors

T. P. Shevlyukova

Tyumen State Medical University

Email: bula.1977@mail.ru
ORCID iD: 0000-0002-7019-6630

DSc (Medicine), Professor of the Department of Obstetrics and Gynecology of the Institute of Maternity and Childhood

Russian Federation, Tyumen

I. A. Bulatova

Tyumen State Medical University

Author for correspondence.
Email: bula.1977@mail.ru
ORCID iD: 0000-0002-7802-4796

DSc (Medicine), Head of the Department of Normal Physiology, Professor of the Department of Faculty Therapy No. 1

Russian Federation, Tyumen

V. E. Vladimirsky

Ye.A. Vagner Perm State Medical University

Email: bula.1977@mail.ru
ORCID iD: 0000-0001-6451-9045

DSc (Medicine), Head of the Department of Faculty Therapy No. 1

Russian Federation, Perm

E. N. Smirnova

Ye.A. Vagner Perm State Medical University

Email: bula.1977@mail.ru
ORCID iD: 0000-0003-2727-5226

DSc (Medicine), Head of the Department of Endocrinology and Clinical Pharmacology

Russian Federation, Perm

E. S. Trofimova

"Alternativa Perm" Clinic

Email: bula.1977@mail.ru

Reflexologist, Expert of the BRICS Health Coalition Association, Neurologist, Director of the Clinic

Russian Federation, Perm

A. A. Yusupova

"Alternativa Perm" Clinic

Email: bula.1977@mail.ru

Therapist

Russian Federation, Perm

References

Supplementary files