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Non-alcoholic fatty liver disease (NAFLD) is a common chronic A progressive disease that affects approximately 24% of the world’s population. Typically, NAFLD is caused by the accumulation of fat in the liver in the absence of metabolic disturbances, infections, lipogenesis, drugs, or heavy alcohol consumption.

Although obesity is one of the important risk factors for the development of NAFLD, NAFLD and obesity are not inseparable. Research has shown that even in the absence of insulin resistance, type 2 diabetes and related metabolic comorbidities, many normal-weight individuals develop NAFLD.

A recent review published in Diabetology & Metabolic Syndrome summarized the The odds, clinical features, and health outcomes of NAFLD were analyzed, and five possible factors for the development of NAFLD in thin people were analyzed, of which diet was an important evaluation factor. In addition, the review discusses existing screening and treatment strategies.

Screenshot source: Diabetology & Metabolic Syndrome

How many thin people are likely to have NAFLD?

The paper points out that body mass index (BMI) is a commonly used indicator to assess fat and thinness However, due to the differences in the physiological and pathological characteristics of different regions and ethnic groups, the BMI thresholds for defining thin people are different in different countries and regions. For example, for Asian and Pacific Island residents, thin people are defined as BMI<23kg/m2; in European populations, it is defined as BMI<25kg/m2.

Overall, the prevalence of NAFLD ranges from 5% to 34%, and the prevalence of NAFLD in lean individuals is approximately 11.0% ~12.6%. In China, the probability of NAFLD in non-obese people was 19.3%, and in Japan it was 15.2%; in Belgian non-obese and non-diabetic people, the prevalence of NAFLD was 2.8%.

The prevalence of thin individuals varies widely across regions, possibly related to the methods used to diagnose NAFLD, such as liver biopsy, abdominal ultrasonography, computed tomography, liver function tests (i.e. liver transaminases), magnetic resonance imaging, etc.; may also be related to the year and sample size of data collection.

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What are the manifestations and outcomes of NAFLD in thin people?

In general,Lean people with NAFLD have a better metabolic profile than people with a higher BMI. Their waist circumference, fasting blood glucose, assessment of insulin resistance (HOMA-IR), and metabolic markers such as triglyceride, HDL-C (high-density lipoprotein cholesterol), and adiponectin levels, It appears to be somewhere between thin people without NAFLD and obese people with NAFLD.

Notably, studies have shown that lean individuals with NAFLD progress to NASH (non-alcoholic) despite having a better metabolic profile. The risk of steatohepatitis) is almost equal to that of overweight or obese patients with NAFLD. The probability of developing NASH is 42% to 50% in thin people, and 68.8% in people with higher BMI. Furthermore, people with a normal BMI have similar risks of liver cirrhosis, malignancy and cardiovascular events as overweight and obese people. This suggests that normal BMI does not prevent disease progression and liver function deterioration.

However, studies have also shown that lean people with NAFLD develop steatosis, lobular inflammation, The risk of ballooning and advanced liver fibrosis was significantly reduced; however, the risk of metabolic disease may be similar to that of obese patients with NAFLD.

Hepatocyte ballooning is more common in viral hepatitis and various types of cirrhosis. Mainly due to the damage of liver cells, the increase of water causes liverThe cells swelled and the cytoplasm became loose, and further developed into hepatocytes swelled as spherical.

US population study data show all-cause mortality in lean people with NAFLD compared to lean people without NAFLD Significantly higher (17.9% vs 40.9%, P<0.001), among which malignancy, cardiovascular disease and infection were the most common causes of death. Data from the Austrian study showed that lean people with NAFLD had a significantly increased risk of fatal liver-related events compared with NAFLD patients with higher BMI.

In summary,Compared with NAFLD patients with higher BMI, although lean people with NAFLD had lower levels of obesity, dyslipidemia severity and liver aminotransferase levels, but patients may be at increased risk for cardiovascular disease, malignancy, progressive liver disease, and related mortality. The reasons for this relative increased risk are unclear and may depend on the underlying pathogenesis of NAFLD in lean individuals.

Image source: 123RF

Why do thin people suffer from NAFLD?

The development of NAFLD in the absence of excessive obesity may have many factors (as shown in the figure below), such as environmental factors, genetic susceptibility, endocrine and metabolic factors, etc. Some factors also interact with each other.

▲ Potential causes of NAFLD in thin people, picture source: Reference [1]

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Environmental (dietary) factors

The study indicated that excessive intake of fructose, refined carbohydrates, sugar-sweetened beverages, saturated fat and animal protein was a major factor in the development of NAFLD. Regular consumption of fructose induces hepatic lipogenesis and endoplasmic stress, impairs fatty acid oxidation, depletes beneficial bacteria in the gut, and causes liver inflammation through the production of uric acid and gut-derived endotoxins. Indirectly lead to insulin resistance in the liver.

Higher dietary choline intake is associated with a lower risk of NAFLD in lean individuals. The appropriate intake of choline is 550 mg/day for men and 425 mg/day for women. Choline is usually higher in animal foods, and people who eat vegetarian food for a long time may be more prone to choline deficiency. Studies have shown that choline can improve liver damage, but choline deficiency for 42 days can lead to significant liver dysfunction in men and postmenopausal women.

Drinking and smoking may also be associated with NAFLD. Alcohol consumption (even in small amounts) and smoking are not only associated with an increased risk of cardiovascular disease and cancer, but also with survival and worsening of liver fibrosis in patients with NAFLD. The study noted that Chinese men with heavy smoking and moderate alcohol consumption had an 85% higher risk of NAFLD compared with those who neither drank nor smoked.

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genetic susceptibility

Although obesity is the strongest independent risk factor for NAFLD, some people with severe obesity and chronic caloric excess do not develop NAFLD . This is because genetic factors are also one of the important risk factors for NAFLD, the most important of which is PNPLA3 (containing patatin-like phospholipids) Enzyme domain 3) gene mutation; in addition, MBOAT7(the gene encoding lysophosphatidyl alcohol acyltransferase), PEMT< Mutations in span> (which can affect choline requirements) and TM6SF2 (a gene primarily responsible for lipid metabolism in the liver) are also associated with NAFLD.

In addition, lipodystrophies (Lipodystrophies, also known as lipodystrophies) also It leads to a variety of adverse complications, including NAFLD and liver fibrosis. Lipodystrophy is a group of rare genetic disorders with a common phenotype of adipose tissue deficiency, or increased metabolism. Gene mutations associated with lipodystrophy include PPARG(peroxisome proliferator-activated receptor gamma), LMNA( Lamin A/C), LIPE (hormone-sensitive lipase, hormone-sensitive lipase) et al.

insulin resistance

As mentioned above, eating too much of foods like fructose and carbohydrates may indirectly lead to insulin resistance in the liver, which can contribute to NAFLD development. In addition, lower expression of hepatic PEMT and conditions such as lipodystrophy are inextricably linked to insulin resistance.

Endocrine changes

NAFLD can progress in the context of endocrine disturbances, both in lean and obese individuals, often associated with hormone-related metabolic changes. For example, women are at high risk for NAFLD and NASH after the menopausal transition; hyperthyroidism may also cause NAFLD. Studies have shown that thyroid hormone supplementation can improve liver dysfunction.

other factors

Other potential factors for NAFLD in lean people include intestinal dysbiosis, parenteral nutrition, malnutrition, and lipogenesis-related drugs (specific steatogenic medications).

In addition, the various factors influence each other. For example, higher intakes of fat or fructose can synergistically enhance the effects of estrogen deficiency, thereby aggravating liver cell damage. The interaction between choline deficiency and hormone levels may increase NAFLD risk. Decreased endogenous estrogen production leads to decreased PEMT gene expression, which may predispose postmenopausal women with chronic cholinergic deficiency to NAFLD.

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Thin Man How to screen for and manage NAFLD?

There is currently no global consensus on the screening and management of NALFD in lean individuals. In the management of NAFLD, whether to distinguish between thin and obese patients still needs more research and exploration.

A practice guidance statement developed by the American Association for the Study of Liver Diseases (AASLD) recommends that, because of tests to support the diagnosis, treatment options, and long-term benefits of screening Not sure yet, and routine screening for NAFLD is not recommended for high-risk groups (ie, those with type 2 diabetes or obesity). Conversely, European and Asian guidelines recommend that screening of individuals at high risk for NAFLD be considered.

Experts also recommend the use of liver function tests and abdominal ultrasonography to screen high-risk individuals, and the use of imaging or predictive algorithms to assess whether patients have liver fibrosis and subsequent diagnosis and staging of NASH. Screening and treatment of NAFLD in lean people are not directly addressed in most guidelines.

NAFLD in lean people is often treated similarly to obese NAFLD patients, with lifestyle changes and weight loss being critical. Reduction of just 5% of initial body weight results in remission in 75% of individuals with NAFLD; 5% body weight loss results in significant improvements in aspartate aminotransferase and alanine aminotransferase levels, as well as liver fat Degeneration and stiffness of the liver.

The review pointed out that relevant research is urgently needed to explore SGLT2 (sodium-glucose transporter 2) inhibitor, GLP-1 (glucagon-like peptide-1) receptor Potential effectiveness of drugs such as agonists, obeticholic acid, pioglitazone, or saroglitazar (PPAR-alpha/gamma dual agonists) in lean people with NAFLD. More studies are expected to identify the underlying genetic factors in non-obese NAFLD patients and to reveal the interaction of lifestyle factors.

Image source: 123RF

Summary

It is not uncommon for thin people to suffer from NAFLD and NASH, which may be related to a variety of factors. Understanding the patient’s menopausal status, genetic factors, dietary factors (especially intake of added sugars, refined carbohydrates, and saturated fat/cholesterol), choline deficiency, and alcohol consumption patterns may be useful in assessing lean individuals There is value in NAFLD risk. Understanding the long-term consequences of NAFLD in lean individuals and the rate and severity of progression to NASH is also important for developing precise treatment strategies.

Review points to the need to increase practitioner awareness of the potential health risks associated with NAFLD in thin individuals; efforts to develop screening algorithms and implement precision treatments based on underlying pathology are warranted strategies to reduce the burden of NAFLD. Early detection of the disease, combined with appropriate measures to alleviate NAFLD through lifestyle changes and clinical interventions, can effectively prevent lean people from developing NASH.

References

[1] DiStefano, J.K.,Gerhard, G.S. (2022). NAFLD in normal weight individuals. Diabetol Metab Syndr 14, 45. https://doi.org/10.1186/s13098-022-00814-z< /p>

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