Physical Exercise and Changes in AST/ALT Rates in Non-Alcoholic Fatty Liver Disease: A Systematic Review of Clinical Trials

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is a pathology resulting from the excessive accumulation of triglycerides in the liver (1). Because it is one of the most common forms of liver involvement, affecting approximately 25% of the world's population (2), it can be considered a public health problem (1,3). The pathophysiology of NAFLD stems from a triad of mechanisms: metabolic, environmental, and genetic (4,5).

The manifestation of NAFLD is characterized by different types of staging, ranging from steatosis, which is the accumulation of fat inside hepatocytes, to cellular hepatocarcinoma, which is the primary cancer of hepatocytes (6). In this aspect, lies the importance of studying and investigating NAFLD, since it has evolutionary potential for necrotizing cells (1).

Among the various diagnostic methods for NAFLD, ultrasonography is the most accessible and available imaging test, however, liver biopsy is the gold standard for diagnosis and stratification of NAFLD (7,8). However, its recommendation is for patients who have elevated liver enzymes, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), for more than three months (1).

AST and ALT are enzymes present in liver hepatocytes, cardiac and skeletal muscles, kidneys, brain, pancreas, lungs, and red blood cells, with ALT being more specific for liver injury (9). When there is liver damage, these are the enzymes most commonly found in liver tests, being essential for the diagnosis and monitoring of liver diseases (1,9,10). However, acute conditions may show higher values ​​and lower/normal values ​​may reflect chronic hepatitis (1,2).

Thus, regardless of the imaging exam, the measurement of liver enzymes and functions, such as AST and ALT, is essential to carry out a differential diagnosis of NAFLD with other pathologies that affect the liver, and it is important to show that transaminases may be elevated or within limits normal values (1,11). Furthermore, the AST and ALT transaminases, which are present in organs such as the liver, muscle, and brain are important biomarkers for configuring liver damage, since their release generates an inflammatory condition (8).

The treatment of NAFLD is based on the control of risk factors, such as obesity, diabetes mellitus, and dyslipidemia, to stagnate the evolution of the disease and reduce inflammatory markers (12). Thus, changes caused by physical exercise in the inflammatory response and the patient's immunological behavior interfere with the inflammatory liver parameters AST, and ALT (9).

Thus, it is important to emphasize that the practice of strenuous physical exercises can increase the AST by up to three times, however, when practiced routinely, aerobic exercise can reduce the ALT by up to 20% (10). This relationship between AST and ALT in response to physical exertion is due to increased cell membrane permeability, lysosomal activity, and sarcoplasmic disruption and vacuolation (9,13).

In this scenario, this review aimed to investigate and summarize how much aerobic and resistance exercise affects the behavior of AST and ALT proteins in the NAFLD spectrum.

2. Materials and Methods

Eligibility Criteria

Articles included were those that met the eligibility criteria, namely (1) clinical trials and (2) assessment of the effect of physical exercise on NAFLD on liver enzymes AST and ALT. Furthermore, there was no restriction on language or period of publication. Exclusion criteria were (1) studies that had samples composed of animals or underage people, and (2) studies in which the population had some other clinical condition associated with NAFLD.

Source of Data Used

The metadata search was carried out using the PubMed, Scopus, Embase, and Cochrane databases, covering publications in Portuguese, English, and Spanish. The descriptors were identified from the MESH search, in addition to the use of keywords related to the theme. The search strategy for the non-alcoholic fatty liver disease (NAFLD) variable and their respective descriptors was: ((((Resistance Training) OR (Endurance Training) OR (resistance exercise) OR (Walking)))) AND (((Non -alcoholic Fatty Liver Disease) OR (Nonalcoholic Fatty Liver) OR (Non-alcoholic steatohepatitis))).

Data Extraction Methods

Data extraction from articles was performed by two independent reviewers. The selection of articles took place in two stages, the first of which consisted of reading the title and abstract based on predetermined keywords. The second step was to read the articles in full from the inclusion and exclusion criteria. After analyzing the eligibility, the data were extracted and a file containing the variables of interest was built using Microsoft Excel, version of the year 2010. Furthermore, a manual search was performed, in addition to reading the bibliographic references of the articles already selected to identify possible studies that could be added.

The results of the selection stages were compared between the two reviewers and disagreements were resolved based on the reading of a third reviewer. All articles presented as a form of evaluation of NAFLD imaging examination, and which obtained ALT and AST enzymes as the main outcome were extracted.

Study Design

This systematic review was registered in PROSPERO with ID CRD42021271707, the international database of systematic reviews in health and social care of the Center for Reviews and Dissemination at the University of York.

Quality of studies

The methodological quality of each included study was assessed using the Cochrane risk of bias tool, which includes the items: sequence generation; participant allocation concealment; blinding of participants and evaluators; blinding of outcome evaluation; incomplete outcome data, and reporting bias. Studies were classified as low risk of bias, unclear, or high risk of bias.

3. Results

Selection of Studies

The primary flowchart (Figure 1) demonstrates how the process of searching and identifying the studies to be included in this systematic review. Initially, 1880 studies were identified and 24 met the eligibility criteria to be included.

Methodological Quality Assessment and Risk of Bias Rating

The methodological quality assessment and risk of bias rating of these clinical trials were analyzed using the Pedro scale and the Cochrane Collaboration Tool (Table 1 and Figure 2).

Characteristics of the Studies

Table 2 contains all the characteristics of the 24 clinical trials included in this systematic review, with a total of 1141 participants aged between 20 and 82 years. These studies were published until the year 2021 and evaluated the effect of physical exercise on AST/ALT liver enzymes.

Types of Intervention

The studies carried out different physical activity intervention protocols, including aerobic exercise, resistance exercise, and both combined. In some studies, a diet was prescribed for the participants, either associated with some physical activity or placed individually as an intervention for one of the groups of some of the analyzed studies.

Types of Variables

The two main outcomes analyzed were ALT and AST liver enzymes. It is worth mentioning that both enzymes are responsible for translating the functioning status of the liver, an organ that can be compromised in people with NAFLD.

Physical Activity Protocol

Intervention protocols varied about the physical exercise application method. They had an intervention interval between 4 – 24 weeks, while the methodology for the exercise protocol varied in intensity. Some groups performed aerobics on treadmills, fixed bicycles, cycle ergometers, and street races. On the other hand, resistance varied according to muscle groups and exercise intensity. Furthermore, the weekly frequency ranged from 2-6 times a week with a duration between 20-90 minutes and intensity between 50-90% of peak VO2 and/or maximum heart rate (HR), depending on the applied protocol.

4. Discussion

This systematic review evaluated clinical trials that analyzed the effect of physical exercise on AST and ALT liver enzymes. In the present study, the intragroup and intergroup analyzes demonstrated that ALT and AST presented different results, and in some studies, physical exercise resulted in the decrease of these enzymes and, in others (14,15), there was no change in these enzymatic parameters.

These enzymes, AST and ALT, can impact in many ways the mechanisms related to non-alcoholic fatty liver disease, since the interaction of factors such as diet, sedentary lifestyle, obesity, lipotoxicity, oxidative stress, and adipokine dysregulation, form a favorable environment for the progression of hepatic steatosis (5,8). In addition, the study by Pinto et al, 2015 that performed serum ALT and AST analyses showed that inactive men had increased serum levels of these liver enzymes when compared to active men, which inferred a greater risk of development of hepatic steatosis, precisely because of this propitious scenario for disease progression (16).

A study conducted by Munhoz et al, 2020 carried out an analysis of medical records of male patients, pointing out that AST and ALT showed a reduction when performing dietary intervention and physical activities (17). Still in this sense, the study by Xiong et al, 2021 demonstrated that individuals who performed aerobic exercise combined with load training, when compared to individuals who did not do any exercise, were able to significantly reduce the level of ALT (18). Thus, the literature review by Kwak, 2018 et al found that aerobic exercises are essential for improving levels of liver injury markers (19).

Aerobic exercise improves NAFLD by increasing lipolysis in different tissues, regulating the uncoupling of protein-1 and peroxisomes, and altering the levels of adipokines (19). In addition, greater regularization of ALT levels was verified in subjects who performed moderate-intensity aerobic exercises as an intervention (19).

Despite that, it is possible to observe that some of the aerobic and resisted physical exercise protocols addressed in this systematic review do not generate significant changes in the AST and ALT parameters (14,15,18,20–23). Of the 24 studies included, six showed improvements in both enzymes in the intervention group, either because one of the two enzymes was not measured or because when there was a change in these values, it was not significant (24–29).

The studies included in this systematic review that showed improvement in both AST and ALT parameters was the study by Takahashi (2017) in which there was a significant decrease in the group that performed resistance training. In the group that performed moderate-intensity aerobic exercise, in the study by Preetam Nath (2020), there was also a significant decrease in AST and ALT (26,29). In the study by El Kader (2014) (25), there was a decrease in AST and ALT levels both in the group that performed moderate aerobic exercise and in the group that performed resistance training. In the study by Shamsoddini (2015) (24), there was a decrease in AST and ALT in the group that performed aerobic exercise and in the group that performed resistance training, both when compared to the control group. And finally, in the study by El Kader (2016) (27), there was also a decrease in AST and ALT in the group that performed aerobic exercise.

Resistance exercise can modify NAFLD through hypertrophy of type II muscle fibers, increasing myokine levels, and activating glucose transporters 4, AMP-Ks (19,30). Additionally, resistance exercise was able to reduce inflammatory markers related to NAFLD with lower total energy expenditure compared to aerobic energy expenditure (19,31). An inverse association was found between the level of physical activity and the prevalence of NAFLD, regardless of the area of ​​visceral fat and insulin resistance (19).

In addition, it is essential to highlight that the best form of non-pharmacological treatment for NAFLD is through weight loss and lifestyle changes (32). This improvement in NAFLD parameters is corroborated by the results of previous studies, such as one that portrayed the significant decrease in the AST and ALT parameter that occurred in the group that performed resistance physical exercise and in the group that practiced physical exercise. resistance associated with curcumin supplementation (33). Furthermore, one of the studies that also showed a significant reduction in both AST and ALT, occurred in the group that performed the physical exercise with a weekly frequency of 5-6 times for 50-60 minutes for 6 months, with an intensity moderate equivalent to activities with MET between 3-5.9 (26).

Thus, it is clear that even though there is no standardization of physical exercise protocols in the included studies, the principle that physical exercise is essential to promote AST and ALT reduction is reinforced, as occurred in the study by Shamsodinni (2015) in that both transaminases were reduced in both exercise groups compared to controls (24). In addition, the study by El Kader (2016) also showed a decrease in AST and ALT in the group that performed physical activity, when compared to the control group (27). Thus, it is noticeable that AST and ALT transaminases, important biomarkers of cellular damage and a liver inflammatory condition, a scenario that occurs in NAFLD, may decrease in some physical exercise protocols, at the moment when aerobic and resistance exercises demonstrated similar effects in the improvement of NAFLD, despite occurring through different mechanisms (8,19,34).

In conclusion, there is controversial evidence, with the implication that there is no significant change in the behavior of the hepatic parameters of AST and ALT when analyzed in individuals diagnosed with NAFLD who were submitted to the practice of aerobic and resisted physical exercises.