Prevalence, proportions of elevated liver enzyme... : Journal of Gastroenterology & Hepatology (original) (raw)

Introduction

Cardiovascular diseases, diabetes, hypertension, and metabolic syndrome are major noncommunicable diseases (NCDs) with a long duration and slow progression, making them considerable public health challenges. NCDs are the leading cause of deaths worldwide; they are responsible for at least 70% of all deaths annually. Fatty liver disease is highly associated with major NCDs and places major health and economic burdens on patients, their families, and society.

A panel of international clinical experts proposed a new nomenclature of fatty liver disease, namely, metabolic dysfunction‐associated steatotic liver disease (MASLD), to describe individuals with steatotic liver disease. The definition offers a more affirmative and non‐stigmatizing description of the condition. In addition, it takes into account the amount of alcohol intake to further classify steatotic liver disease. Estimation of the prevalence of MASLD, particularly according to various cardiometabolic characteristics, is key to characterizing clinically relevant subgroups and allocating health‐care resources.

Fatty liver disease is the most prevalent liver disease and affects almost 2 billion people globally. It is therefore challenging to identify high‐risk patients for referral to intense clinical management. Elevated serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are indicative of hepatocellular injury. Elevated concentrations of liver enzymes indicate a significantly heightened risk of cirrhosis and hepatocellular carcinoma, ; thus, the measurement of liver enzyme concentrations can assist with risk stratification and disease surveillance. However, the clinical impact of liver enzyme levels, particularly on the identification of high‐risk individuals with cardiometabolic diseases among patients with MASLD, requires further investigation. In addition, the long‐term risks of all‐cause and cardiometabolic‐specific mortality associated with MASLD and elevated liver enzyme levels have rarely been evaluated.

In a large‐scale study with 343 816 participants receiving health examinations, we investigated the overall prevalence of MASLD and that within cardiometabolic subgroups. In addition, we conducted a cross‐sectional examination of the associations of MASLD, as indicated by elevated liver enzyme levels, with cardiometabolic comorbidities. Liver enzyme levels were also evaluated regarding the associated risks of long‐term all‐cause, cardiovascular‐related, and diabetes‐related mortality.

Methods

Study population and data collection

The 421 919 study participants were healthy individuals aged ≥30 years who participated in a health screening program managed by a private health‐care institution in Taiwan. All participants were followed up from 1997 through 2013. The participants received a series of blood, urine, and anthropometric tests and physical examinations after study enrollment. At enrollment, each participant completed a structured questionnaire on sociodemographic characteristics, lifestyle, and personal and family histories of major diseases. Blood samples were subjected to virological and biochemical tests such as those for hepatitis B surface antigen (HBsAg), antibodies against hepatitis C virus (anti‐HCV), triglycerides, cholesterol, and liver enzymes. Every participant provided signed informed consent regarding the use of data generated from medical screenings for biomedical investigations. The study protocol was approved by the Institutional Review Board of National Yang Ming Chiao Tung University, Taipei, Taiwan.

Definition of liver steatosis subtype: MASLD

Each of the study participants was examined by board‐certified gastroenterologists using high‐resolution real‐time abdominal ultrasonography. The presence of steatosis within the hepatic parenchyma was assessed according to parenchymal brightness, liver‐to‐kidney contrast, deep beam attenuation, and bright vessel walls. The participants were restricted to those with limited alcohol intake (<10 g/day for women and <20 g/day for men by Asian‐Pacific Guidelines). MASLD was defined as the presence of steatotic liver disease (SLD) with the presence of at least one cardiometabolic risk factor according to the international expert consensus statement. The cardiometabolic risk factors included the following: central or overall obesity, type 2 diabetes mellitus, hypertension, hypertriglyceridemia, and low high‐density lipoprotein‐cholesterol. We further categorized individuals with MASLD using liver enzyme levels. An elevated liver enzyme level was defined as either a high serum concentration of AST (≥37 U/L in men or ≥31 U/L in women) or a high serum concentration of ALT (≥40 U/L in men or ≥31 U/L in women)., ,

Definition of cardiometabolic diseases at baseline

The presence of various cardiometabolic diseases at baseline was defined as follows: Diabetes was indicated on the basis of a patient having a preprandial glucose level of ≥126 mg/dL, self‐reported diabetes, or an antidiabetic drug prescription. Cardiovascular disease was indicated on the basis of a patient self‐reporting cardiovascular disease, taking related medication, or having a Framingham risk score in the 90th percentile (men: >17; women: >14). Hypertension was indicated on the basis of a patient having high blood pressure (≥140/90 mmHg), self‐reporting hypertension, or taking related medication. Hyperlipidemia was indicated on the basis of a patient having elevated total cholesterol or triglycerides levels (≥200 mg/dL or ≥130 mg/dL), self‐reporting hyperlipidemia, or taking lipid‐lowering drugs. Metabolic syndrome was defined according to the revised National Cholesterol Education Program's Adult Treatment Panel III.

Confirmation of all‐cause and cardiometabolic condition‐related deaths

Registration of the deaths of all citizens in a computerized database is mandatory in Taiwan. National Death Certification Registry profiles contain information on the cause and date of death, and they have been applied in several key outcome‐based studies. Death certificates must be registered within 1 month after a death in Taiwan. All death certificates are coded and reviewed by medical coders in the central office. The death certification system maintains updated and complete information on the vital status and cause of death of all inhabitants of Taiwan. National identification number, date of birth, and sex were used as linking variables to verify the vital status and causes of death of the study participants from the National Death Certification system. All deaths that occurred between study entries to December 31, 2020, were included.

Statistical methods

Baseline profiles of the study participants are displayed in terms of the presence or absence of MASLD. The prevalence of MASLD with a 95% confidence interval (CI) was estimated using various baseline characteristics and cardiometabolic comorbidities. The proportions of abnormal serum liver enzyme levels according to baseline characteristics among patients with MASLD were estimated and compared using chi‐squared tests. To assess the effects of serum liver enzyme levels on cardiometabolic comorbidities and long‐term mortality among MASLD patients, we excluded non‐SLD individuals with abnormal liver enzyme levels using non‐SLD individuals with normal liver enzyme levels as the reference group. Logistic regression models were used to estimate the odds ratios (ORs) with 95% CIs of the associations of MASLD with or without abnormal liver enzyme levels on cardiometabolic comorbidities. To evaluate the long‐term impact of MASLD and abnormal liver enzyme levels, all‐cause, cardiovascular, and diabetes mortality levels were assessed. Cox proportional hazards models were used to obtain crude and adjusted hazard ratios (HRs) with 95% CIs for the risk of mortality associated with MASLD. The proportionality assumptions (nonchanging HRs over time) of the Cox models were examined and were not violated. To determine the covariates included in the models, we considered confounding factors associated with various cardiometabolic comorbidities. Our initial step is to identify potential confounders significantly associated with the specific outcome in the univariate regression models. We then assessed collinearity among the variables, excluding those exhibiting high correlations. The remaining covariates were included in the multivariate adjustment. Subsequently, nonsignificant variables were systematically ruled out, resulting in final multivariate‐adjusted models containing only significant covariates. We also applied Cochran–Armitage trend tests to investigate the risk of death in individuals without SLD, with MASLD and normal liver enzymes, or with MASLD and elevated liver enzymes. A two‐sided P value of <0.05 indicated significance. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA) or R packages.

Results

Baseline participant characteristics

The study flowchart is displayed in Figure 1. After the exclusion of individuals lacking sufficient information for the identification of MASLD or who died <6 months after enrollment, 343 816 individuals were included in the study. Among them, 128 498 (37.4%) had steatosis identified through abdominal ultrasonography. We further classified these participants by their BMI and diabetes and metabolic profiles; 123 280 (95.9% of 128,498) were classified as having MASLD. The baseline characteristics of individuals with MASLD are displayed in Table 1. Compared with patients without MASLD, a higher proportion of those with MASLD had advanced age, had elevated BMI, were men, were current smokers (P < 0.001). In addition, patients with MASLD had more cardiometabolic comorbidities including cardiovascular disease, hypertension, hyperlipidemia, and metabolic syndrome (P < 0.001).

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Figure 1Open multimedia modal

Flowchart of study population. CMRF, cardiometabolic risk factors; MASLD, metabolic dysfunction‐associated steatotic liver disease; SLD, steatotic liver disease. Abnormal liver enzyme: ALT ≥ 31 and AST ≥ 31 for female and ALT ≥ 40 and AST ≥ 37 for men.

Prevalence of MASLD according to cardiometabolic characteristics

Overall, the prevalence of MASLD was 36.4% (27.2% for women and 48.2% for men; Fig. 2a). The prevalence of MASLD was higher in older individuals, those with a high BMI, and smokers. Individuals with cardiometabolic comorbidities, including diabetes, cardiovascular disease, hypertension, hyperlipidemia, and metabolic syndrome, had a high prevalence of MASLD, ranging from 49.0% to 79.8%. Of participants without any cardiometabolic comorbidity, 15.9% were classified as having MASLD.

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Figure 2Open multimedia modal

(a) Prevalence of metabolic dysfunction‐associated steatotic liver disease according to baseline cardiometabolic characteristics. (b) Proportions of patients with metabolic dysfunction‐associated steatotic liver disease who had normal and abnormal liver enzyme levels.

, MASLD/normal liver enzymes;

, MASLD/abnormal liver enzymes.

Distribution of abnormal liver enzymes among patients with MASLD

In total, 35.9% of patients with MASLD and 10.6% of patients without steatotic liver disease had abnormal liver enzyme levels. The proportions of MASLD patients with normal and abnormal liver enzyme levels according to baseline characteristics are displayed in Figure 2b. The proportion patients with abnormal liver enzyme levels decreased with age (P < 0.001). More individuals who were obese (BMI > 25 kg/m2) had abnormal liver enzymes than those in other BMI groups (P < 0.001). Abnormal liver enzyme levels were associated with the presence of diabetes, hyperlipidemia, metabolic syndrome, or at least one cardiometabolic comorbidity (P < 0.001). In total, 34.1% and 46.2% of individuals without or with chronic hepatitis B or C virus, respectively, had abnormal liver enzymes (P < 0.001).

Association of cardiometabolic diseases with MASLD and liver enzyme levels

As shown in Table 2, MASLD was significantly and positively associated with the presence of diabetes, cardiovascular diseases, hypertension, hyperlipidemia, or metabolic syndrome, with an adjusted OR of 1.24–4.27 (P < 0.001). Compared with non‐SLD individuals who had normal liver enzyme levels, individuals with MASLD had a 2.84‐fold (2.78–2.91) higher likelihood of having a cardiometabolic comorbidity. In addition, individuals with MASLD with normal or abnormal liver enzyme levels had a higher risk of diabetes, cardiovascular disease, hypertension, hyperlipidemia, and metabolic syndrome than those non‐SLD and normal liver enzyme levels, with the adjusted ORs ranging from 1.23 to 6.44 (all P < 0.001). Participants with MASLD and normal and abnormal liver enzyme levels had a 2.36‐fold (2.30–2.41) and 4.50‐fold (4.34–4.66) higher risk, respectively, of having any of the aforementioned comorbidities, compared with the reference group (P for trend < 0.001).

Risk of all‐cause and cardiometabolic‐specific mortality associated with MASLD and liver enzyme levels

The crude and adjusted HRs and 95% CIs for all‐cause and cardiometabolic‐specific mortality by MASLD status are shown in Table 3. Individuals with MASLD had a higher risk of all‐cause mortality than those without, with an adjusted HR of 1.09 (1.06–1.12). The risk of cardiovascular mortality was 11% higher among participants with MASLD than among those without (95% CI: 1.05–1.18). The risk of diabetes‐specific mortality was 1.29 times higher among patients with MASLD (95% CI: 1.03–1.60). Compared with patients without MASLD and normal liver enzyme levels, those with MASLD with normal and abnormal liver enzyme levels had a significantly higher risk of all‐cause mortality (P for trend < 0.001), with an adjusted HR of 1.02 (0.99–1.06) and 1.28 (1.23–1.32), respectively. Similarly, the risks of cardiovascular‐ and diabetes‐specific mortality were significantly higher in those with MASLD with abnormal and normal liver enzyme levels than in those without MASLD (P for trend < 0.001).

Discussion

This study demonstrated that the prevalence of MASLD ranged from 49.0% to 79.8% among patients with various cardiometabolic factors. MASLD and elevated liver enzymes were positively associated with the presence of cardiometabolic comorbidities. Furthermore, the presence of MASLD with elevated liver enzyme levels was significantly associated with long‐term risks of all‐cause, cardiovascular, and diabetes‐specific death. These findings suggest that liver enzyme levels could be used for the MASLD risk stratification and the referral of patients with MASLD for cardiometabolic consultations. Elevated enzyme levels in patients with MASLD should be monitored during clinical follow‐up, which may help prevent health problems beyond liver disease.

The initial definition of nonalcoholic fatty liver disease (NAFLD) lacks positive criteria for key metabolic features. In contrast, the diagnostic criteria of metabolic dysfunction‐associated fatty liver disease (MAFLD) include the presence of metabolic risk factors along with hepatic steatosis, including other concomitant liver diseases. Studies comparing clinical profiles and outcomes based on NAFLD and MAFLD revealed that NAFLD with known metabolic risk factors was linked to elevated all‐cause mortality., , , , , However, MAFLD's inclusion of individuals with fatty liver, irrespective of alcohol consumption, and its requirement for at least two metabolic risk factors raised concerns about potential misclassification. To address, this, MASLD was introduced, aiming to redefine individuals with SLD and categorize patients into distinct subtypes. Following the adoption of the new term, MASLD, 89.2% of individuals with intrahepatic triglyceride content >5% met the criteria for NAFLD, MAFLD, and MASLD, indicating minimal discrepancies between these definitions.

Because of the differences between the definitions of NAFLD and MAFLD, 80%–90% of individuals with hepatic steatosis meet the criteria for both NAFLD and MAFLD. These results, consistently with our previous study, demonstrated that patients with NAFLD with elevated liver enzymes had a higher risk of advanced liver disease than patients with NAFLD with normal liver enzymes, who had a similar risk to patients without NAFLD. In addition, the current findings suggest that associations of serum liver enzyme levels with mortality might reflect hepatocyte and extrahepatic cell injuries.

Individuals with MASLD and elevated serum liver enzymes had higher risk of baseline cardiometabolic comorbidities and all‐cause and cardiometabolic‐specific mortality than those without. Liver aminotransferases, ALT and AST, can be detected in the liver and in various organ tissues in common laboratory tests used to screen for liver diseases. In addition to all‐cause mortality and advanced liver diseases,, studies have demonstrated that liver enzyme levels are associated with the risk of type 2 diabetes and cardiovascular diseases. However, elevated liver enzymes can be used as an indicator of fatty liver disease, and a heightened risk of cardiometabolic diseases, as identified in previous studies., Our study directly strengthened the clinical utility of liver enzyme levels for the management of patients with MASLD; elevated liver enzyme levels can serve as a long‐term predictor of diseases or assist with stratification of the risks of several diseases. In the human body, ALT is predominantly present in the liver, and its serum levels are elevated when disease processes affect liver cells. Our findings suggest that increased liver enzymes may reflect subclinical inflammation that enhances tissue damage and susceptibility to the chronic diseases identified in this study. Among participants without ultrasound identified steatotic liver disease, a substantial proportion (10.6%) had abnormal liver enzyme levels. To prevent estimates of the impact of MASLD with abnormal liver enzyme levels on various cardiometabolic comorbidities and mortality from approaching the null, we excluded this subgroup from our comparisons. Future investigations should explore whether participants in this subgroup may have underlying chronic diseases contributing to elevated liver enzyme levels.

Fatty liver disease is strongly correlated with cardiometabolic comorbidities. Our study revealed that individuals with MASLD were 1.24–4.27 times more likely to exhibit baseline cardiometabolic comorbidities than those without. Our findings suggested that numerous individuals without cardiometabolic factors were nonetheless classified with MASLD. In addition, 11.4% of participants with a BMI in the normal range (18.5–22.9 kg/m2) and 45.1% of participants who were overweight (23–24.9 kg/m2) had MASLD, suggesting that the prevalence of nonobese MASLD was considerable in the study population. Individuals with NAFLD and normal BMI have a 63% higher risk of all‐cause mortality than that of individuals without NAFLD despite having a less severe metabolic risk profile, implying that the management of NAFLD in patient with a low or normal BMI is likely to differ from the conventional lifestyle changes implemented for weight loss or control of diabetes, hypertension, or hyperlipidemia. A study demonstrated that lean patients have increased bile acid and fibroblast growth factor 19 levels and exhibit distinct microbiota profiles that mediate resistance to diet‐induced obesity through metabolic adaptations. Although data on long‐term outcomes of lean MASLD are scarce, one Chinese cohort study demonstrated that lean patients with MAFLD had higher rates of metabolic disorders than lean patients with NAFLD. A retrospective study including patients with biopsy‐proven NAFLD demonstrated that 20% of lean patients with NAFLD had steatohepatitis and carotid atherosclerosis, and advanced liver progression was particularly prevalent among those with variations in PNPLA3. Future studies exploring possible risk factors and predictors for long‐term risks of advanced liver diseases and cardiometabolic diseases among lean patients with MASLD are necessary. The impact of each metabolic trait of the diagnostic criteria for lean patients with MASLD must be evaluated to enable proper monitoring.

The study identified that the presence of MASLD increased the risk of cardiometabolic comorbidities and death, particularly among patients with elevated liver enzyme levels. These findings were consistent with clinical practice guidelines indicating that patients with NAFLD should be evaluated and treated for modifiable cardiovascular disease risk factors, including diabetes, dyslipidemia, and hypertension. Maintaining liver enzymes within the normal range is critical, as is the monitoring of MASLD. Lifestyle interventions are effective for treating patients with NAFLD, and weight reduction predicts the remission of NAFLD. Weight loss is also associated with significantly reduced liver enzyme levels. Patients with MASLD should undergo consultation to reduce their weight, enhance physical activity, consume a healthy diet, and modify metabolic risk factors to improve their overall health.

Robust epidemiological data on MASLD and long‐term mortality are limited. The current study included a large and well‐characterized population, with analyses accounting for a wide variety of sociodemographic, clinical, and cardiometabolic risk factors. Long‐term follow‐up provided sufficient time for mortality to occur, and mortality was determined on the basis of reliable nationwide registries. The participants were recruited from a health examination center and were generally healthy, indicating that the findings could be applied to strategies for cardiovascular disease prevention. Unlike in a Korean study, liver fat in current study was measured using abdominal ultrasonography, which yields a higher accuracy than the use of biochemical scores such as the fatty liver index or hepatic steatosis index. The measurement of serum liver enzymes is routinely performed during health checkups, providing relevant indications for the identification of MASLD in patients at an increased risk of cardiometabolic comorbidities for clinical referrals to other specialists. This study will be helpful for guiding clinical practitioners in managing the cardiovascular comorbidities of patients with MASLD. This study has some limitations. Because metabolic abnormalities are dynamic, the presence of MASLD as defined at baseline may have not fully reflected participants' metabolic phenotypes. In addition, the current analyses were based on a single measurement of baseline serum liver enzyme levels; changes may have occurred over time. However, liver enzymes are relatively stable over time, and ALT levels do not fluctuate during the course of a day. In the future, evaluations of clinical outcomes among patients with MASLD incorporating changes in liver enzymes are warranted. During follow‐up, changes in diet and lifestyle habits, medications, and other psychosocial factors may have not been easily controlled for, potentially causing residual confounders to influence assessments of mortality.

In conclusion, abnormal serum liver enzyme levels are positively associated with cardiometabolic comorbidities and long‐term risks of all‐cause and cardiometabolic‐specific mortality among individuals with MASLD. Patients with MASLD should be referred for cardiometabolic disease management. In addition, patients with MASLD should be considered for liver enzyme level monitoring and receive consultations regarding lifestyle modifications and their risk of cardiometabolic diseases.

Acknowledgments

We express our gratitude to Chi Chan and Yu‐Han Huang for their assistance during the initial stages of this study.

References

Keywords :

long‐term risk; nonalcoholic fatty liver disease; noncommunicable diseases