Effects of Physical Activity on Liver Function in
Patients with Non-alcoholic Fatty Liver Disease: A
Jingjing Li, Fan Wang, Kan Chen, Yujing Xia, Jie Lu, Yingqun Zhou, Chuanyong Guo*
Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
Chuanyong Guo, Department of gastroenterology, Shanghai Tenth People's Hospital, Tongji University of medicine,
People's Republic of China, Tel: +86-21-66302535; Fax: +86-21-66303983; E-mail:
Received: October 29, 2015; Accepted: December 02, 2015; Published: December 05, 2015
Li J, Wang F, Chen K, Xia Y, Lu J, et al. (2015) Effects of Physical Activity on Liver Function in Patients with Non-alcoholic
Fatty Liver Disease: A Meta-Analysis. SOJ Immunol 3(5): 1-6. DOI: http://dx.doi.org/10.15226/2372-0948/3/5/00143
Aim: To evaluate the effects of physical exercise in patients with
Methods: We searched standard databases including PubMed,
Cochrane Library, EMBASE, et. al. up to Feb. 2014 to obtain relevant
literatures. The Standard Mean Differences (SMD) with 95%
confidence interval (95% CI) was calculated to estimate the effects.
Results: ALT levels of patients before and after exercise so
significantly reduced that liver function returned to positive (SMD
-0.40, 95% CI -0.75~ -0.05, P = 0.03). The significant differences
observed between the experimental and control groups showed that
exercise can effectively lower fasting blood glucose in patients with
NAFLD (SMD -0.33, 95% CI -0.64 ~ -0.02, P=0.04).
Conclusion: Exercise did not change body weight, but did
improve liver enzymes and blood glucose levels in patients diagnosed
with non-alcoholic fatty liver disease.
Keywords: NAFLD; Physical exercise; Liver fibrosis; Hepatology
Non-Alcoholic Fatty Liver Disease (NAFLD) has been
reported to be associated with the incidence of other chronic
liver diseases, diabetes and atherosclerosis. However, lifestyle
change has significance in the improvement and rehabilitation of
patients. The aim of this meta-analysis was to evaluate the effects
of physical exercise in patients with NAFLD.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a metabolic
stress-induced liver disorder closely related to insulin resistance
and genetic susceptibility. NAFLD is characterized by excessive
fat deposition in liver cells and includes three types: Simple
Fatty Liver (SFL), Non-Alcoholic Steatohepatitis (NASH) and its
related cirrhosis . According to the investigation by Lazo et al.,
the average prevalence rate of NAFLD in adults is approximately
10 to 30%, and up to 25% of patients develop cirrhosis within a
decade [2,3]. In Europe and other developed countries, NAFLD
may affect the incidence of other chronic liver diseases, diabetes and atherosclerosis, and can lead directly to decompensate
cirrhosis. NAFLD can endanger patients' health and lives [4-
6]. Therefore, the identification of an effective intervention to
improve patient quality of life has great significance.
However, most of the drugs administered for NAFLD, such
as the cholesterol-lowering drugs, statins, and antioxidants,
hepatoprotective drugs and insulin-sensitizing agents, have
pharmacological toxicity resulting in side effects. In recent
years, Oza, et al. , concluded that lifestyle changes including
moderate aerobic exercise has significance in the improvement
and rehabilitation of patients. Researchers worldwide have
conducted a number of studies on the effects of exercise; however,
large-scale trials have not been carried out due to limitations on
the prevalence of NAFLD [8-11]. Therefore, in the present study
we performed a meta-analysis of Randomized Controlled Trials
(RCTs) to evaluate the effects of physical exercise in patients with
Data sources and searches
Relevant literature was obtained using standard databases
including PubMed, Cochrane Library, EMBASE, CINAHL, Web
of Science, and Science Citation Index (updated to Sep. 2015),
and was limited to human studies published in English with a
search strategy using the Medical Subject Headings (MeSH) and
text key words"exercise", "non-alcoholic fatty liver disease",
and "randomized controlled trial". We also performed a
comprehensive manual search of all references from primary or
review articles and abstracts to identify valuable studies.
Studies included in this meta-analysis conformed to the
following inclusion criteria:
1. Experimental design: RCTs on the effects of exercise in
patients with NAFLD;
2. Experimental subject: patients with a diagnosis of NAFLD for more than one year identified according to the American
Gastroenterological Association ;
3. Experimental process: the study included a control group,
moderate exercise intensity (exercise of more than 20 min, more
than twice a week), reported data on liver biochemical markers
4. Subjects were excluded due to long-term alcohol
consumption (more than 20g/ d).
Data abstraction and quality assessment
Data abstraction was independently performed by two
investigators (Jingjing Li and Fan Wang) using a standardized
data abstraction tool based on the Cochrane Handbook for
Systematic Reviews of Intervention and any differences were
resolved by consensus or by the third investigator (Kan Chen).
The following information was extracted from each article: name
of the first author, year of publication, sample size, exercise
intensity and period, method of data collection and method used
to deal with missing data, basic parameters (age, sex and body
mass index, BMI) and liver biochemistry (alanine transaminase,
ALT; aspartate aminotransferase, AST) before and after exercise,
and adverse events. Exercise should be as aerobic.
Methodological quality of the studies was assessed by the
Consolidated Standards of Reporting Trials (Consort statement)
. The studies included in the meta-analysis were evaluated
using the 22-stem criteria for RCTs in order to maintain the
high quality of the literature using scientific evaluation for RCT
design. Each item received 1 score, and studies with a score of
more than 18 were considered high quality. Two researchers
evaluated the studies which were included in the meta-analysis
when a consensus was reached. The meta-analysis was carried
out according to the Cochrane Handbook of Systematic Reviews
consistent with PRISMA guidelines .
RevMan 5.2 (The Nordic Cochrane Centre, The Cochrane
Collaboration, 2012) was used to analyze the extracted data.
The Odds Ratio (OR) with 95% Confidence Intervals (CI) for
continuous data was evaluated. Dispersion extent was evaluated
using the Standard Mean Difference (SMD). When the original
literature did not report SMDs, they were assessed by other
literature data. During assessment of data heterogeneity, when
P values were > 0.10 and an I2 value was < 50%, the fixed effects
model was used, otherwise a random effects model was used .
For in-depth study of the clinical heterogeneity of the results, we
established a subgroup analysis as each study reported slightly
different source data and target results. Data heterogeneity may
lead to an exaggerated effect and if all blind inclusions lead to
increased internal validity this could reduce the credibility of the
analysis. We also used funnel plots to determine publication bias
to increase data availability to the highest degree.
We searched 186 papers from the above-mentioned databases, and following strict selection, 5 papers were
included in the study (Figure 1) [8,9,11,16,17]. These studies
included patients with NAFLD enrolled in RCTs with a doubleblind
physical exercise intervention and reported liver function
indices including ALT and AST. The selected papers also included
data on liver histopathology. The basic characteristics and quality
scores of the selected studies are shown in Table 1. Patient
age ranged from 15 to 60years with a different number of patients
in each study. Exercise intensity was moderate and mainly aerobic
exercise. The duration of treatment in each study was different
and ranged from1 week to 6 months. According to Table 1 the
duration of treatment ranged from 2 weeks to 6 months, and the
results were used as an effective reference range.
Five trials [8,9,11,16,17] which included 187 patients
reported changes in body weight using BMI as the
standard. Heterogeneity (P = 0.01, I2 = 69%) was high, but in
the moderate range. Significant clinical heterogeneity was
observed, however changes in the data may have been due
to patient age and different BMIs. Therefore, the random effects
model was used. No statistically significant difference in BMI was
found in patients with NAFLD following exercise (SMD -0.17,
95% CI -0.75 ~ 0.41, P = 0.57; Figure 2).
A total of four trials [8,9,11,12] reported ALT level change
before and after exercise. Analysis of the results using a
fixed effects model synthesis was not statistically significant
heterogeneity (P = 0.33, I2 = 12%), and the description of the
experimental results is homogeneous. We calculated the value
of their combined effect to find that there was statistically
significant between the experimental group and the control. The
differences indicated that ALT levels of patients before and after
exercise so significantly reduced that liver function returned to
positive (SMD -0.40, 95% CI -0.75 ~ -0.05, P = 0.03; Figure 3).
Nonalcoholic fatty liver disease is often seen in patients with
diabetes due to metabolic disorders; therefore, we evaluated
fasting blood glucose reported in four trials [8,9,15,16] which
helped us to recognize NAFLD as a standard indicator for glucose
determination. We found that in170 patients, fasting blood
glucose testing showed no heterogeneity (P = 0.46, I2 = 0%). The
combined effect can be a better representation of the overall level.
The significant differences observed between the experimental
and control groups showed that exercise can effectively lower
fasting blood glucose in patients with NAFLD (SMD -0.33, 95% CI
-0.64 ~ -0.02, P = 0.04; Figure 4).
Changes in blood glucose and ALT in patients with NAFLD
suggested that the patient's condition improved following
exercise; however, the significance of BMI requires further
investigation. Re-validation of the five studies showed that
Figure 1: Trial identification, inclusion and exclusion.
Table 1: Patient demographics.
Duration of treatment
Figure 2: BMI in patients suffered with nonalcoholic fatty liver disease.
Figure 3: ALT level in patients with nonalcoholic fatty liver disease.
Figure 4: Fasting blood glucose in patients with nonalcoholic fatty liver disease.
patient age in one study was lower than that in the other studies,
thus a meta-analysis of the results did not rule out inaccuracies.
This study was excluded and the other four studies were analyzed
again, and no change in BMI heterogeneity (P = 0.73, I2 = 0%) was
noted. These results indicated that the data were not statistically
significant and were still consistent with the above-mentioned
conclusions (SMD 0.12, 95% CI -0.47 ~ -0.7, P = 0.7).
Funnel plot asymmetry of the meta-analysis results showed
the presence of slight publication bias which was caused by the
sample size and treatment effect (Figure 5).
Due to improvements in living standards, fatty liver caused
by obesity, diabetes, hyperlipidemia, and metabolic syndrome
has increased and Non-Alcoholic Fatty Liver Disease (NAFLD)
is a threat to human health. Worldwide research on this disease
has significantly increased in the past few years and researchers
are working to resolve this issue [18-21]. However, identification
of the optimal treatment for NAFLD is a slow process due to
the complexity of the disease. Many patients are faced with the
transition from hepatitis to cirrhosis and even complete liver
failure. Statins and insulin sensitizer therapy administered during
this stage of the disease are ineffective . Generic drugs with
hepatic and renal toxicity can cause damage to other organs in
addition to the liver. Eckard et al. , found that healthy lifestyle
changes including diet, exercise, and daily vitamin supplements significantly improved liver function. However, some researchers
believe that intensive exercise raises oxygen tolerance, in addition
to increased consumption of oxygen [23,24]. Therefore, an anoxic
environment is formed in the body and recovery of liver function
is unfavorable. This study was performed to confirm existing
research results, and included a large sample size to evaluate the
effects of exercise on liver function and blood sugar levels.
Description of research quality
In this study, we conducted rigorous screening to ensure the
inclusion criteria were fair. The selected randomized controlled
trials were chosen due to their strict design and evaluation
results. Two of these studies were small heterogeneous
trials and assessment indicators met the requirements of the
combined effect, thus can be combined in large sample sizes
for statistical analysis to draw accurate conclusions. However,
greater heterogeneity for BMI, analyzed by re-assessment
methods, may have included age as a major factor causing these
differences. Sensitivity analysis showed a low heterogeneity and
a meaningful combined effect when one trial, which resulted
in large differences but negative results, was excluded. Slight
asymmetry in the funnel plots showed publication bias related
to the sample size.
Analysis of results
Patients after a short period of moderate exercise showed
no obvious bias in BMI which illustrated that weight loss was
not obvious when a normal diet was consumed. Meaningful
Figure 5: Funnel plots for the meta-analysis.
reductions in ALT and the glycemic index were observed.
Although this effect did not fully explain the improvements in
liver function and blood lipid levels, the differences between
the exercise group and the control group showed satisfactory
changes to some extent. The main symptoms in NAFLD patients
include bloating, gas and other liver disorders, and elevated
blood sugar which can also lead to elevated blood lipids and a
burden on the liver associated with treatment [25,26]. Delays in
treatment can result in fat deposition in the liver. The present
study found that exercise increased the activity of glycogen
synthase, and affected sequestration of fatty acids and the glucose
cycle in order to reduce the process of de novo lipogenesis [8,27].
Aerobic exercise stimulated the synthesis of triglycerides and
reduced the deposition of fatty acid and its metabolites in the
liver, and prevented the progression of liver fibrosis [11,28].
Currently, the concept of a healthy lifestyle to minimize
damage to the immune system due to drug therapy has great
significance . Exercise is widely performed by healthy
individuals; however, most patients require bed rest and are
unable to benefit from the positive effects of scientific and
standardized exercise until they are well. Although this study
did not explain the relationship between weight loss and
improvement in related diseases, it is thought that exercise
is closely related to disease. In clinical practice, professionals
should actively promote a reasonable exercise program and
urge patients to take part in a progressive exercise program to
encourage the recovery of patients in an economical and effective
Limitations of this study
Although these five studies were high-quality randomized
controlled trials, some limitations existed. For example: (1)
Although we performed the meta-analysis to obtain a large
sample size, the results were limited and further investigations
are required; (2) It is difficult to achieve consistent baseline
parameters due to differences in the populations studied, thus
these differences should be compared to assess the effect on
outcome. However, slight inaccuracies may exist due to the
different measurement methods used. A subsequent study
should standardize baseline parameters to determine the
accurate effects of physical activity; and (3) the assessment of
patients using non-uniform standards resulted in a few combined
indicators which showed little improvement following exercise.
In addition to the assessment of enzymatic and biochemical
changes, personal feelings and psychological quality of life should
also be used as evaluation criteria . Therefore, SDS scores
for depression and anxiety in patients should be included for a
comprehensive evaluation of the extent of disease in patients.
In summary, exercise did not change body weight, but did
improve liver enzymes and blood glucose levels in patients
diagnosed with non-alcoholic fatty liver disease and indicated the
significant importance of exercise in improving patients' health.
Changes in oxygen resistance, lipid levels and liver enzyme levels
improved liver histopathology and delayed disease progression to cirrhosis. Moreover, reduced cost and self-addressed exercise
therapy, facilitated self-treatment of patients, to some extent.
Of course, drug treatment is also necessary combined with
a reasonable diet and moderate aerobic exercise to control
weight, blood sugar, cholesterol and promote reversal of
liver histopathology [31-34]. Therefore, we recommend that
patients with NAFLD undergo regular aerobic exercise to reduce
This study was supported by the Chinese Foundation for
Hepatitis Prevention and Control (Grant nos. TQ20120005).
Li JJ, Zhou YQ and Guo CY designed the research; Li JJ, Wang
F, Chen K, Xia YJ and Lu J analyzed the data; Li JJ wrote the paper.
This study was supported by the Chinese Foundation for
Hepatitis Prevention and Control (Grant nos. TQ20120005).
- Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413-9.
- Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut. 2007;56(12):1760-9.
- Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008;28(4):339-50. doi: 10.1055/s-0028-1091978.
- Kim HJ, Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med. 2004;164(19):2169-75.
- Nyenwe EA, Williamson-Baddorf S, Waters B, Wan JY, Solomon SS. Nonalcoholic Fatty liver disease and metabolic syndrome in hypopituitary patients. Am J Med Sci. 2009;338(3):190-5. doi: 10.1097/MAJ.0b013e3181a84bde.
- Moore JB. Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc. 2010;69(2):211-20. doi: 10.1017/S0029665110000030.
- Oza N, Eguchi Y, Mizuta T, Ishibashi E, Kitajima Y, Horie H, et al. A pilot trial of body weight reduction for nonalcoholic fatty liver disease with a home-based lifestyle modification intervention delivered in collaboration with interdisciplinary medical staff. J Gastroenterol. 2009;44(12):1203-8. doi: 10.1007/s00535-009-0115-x.
- St George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2009;50(1):68-76. doi: 10.1002/hep.22940.
- Eckard C, Cole R, Lockwood J, Torres DM, Williams CD, Shaw JC, et al. Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Therap Adv Gastroenterol. 2013;6(4):249-59. doi: 10.1177/1756283X13484078.
- Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121-9. doi: 10.1002/hep.23276.
- Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. Hepatology. 2012;55(6):1738-45. doi: 10.1002/hep.25548.
- Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592-609. doi: 10.1053/j.gastro.2012.04.001.
- Lorette G, Maruani A. [The CONSORT statement (CONsolidated Standards of Reporting Trials)]. Ann Dermatol Venereol. 2013;140(6-7):431-5. doi: 10.1016/j.annder.2013.04.091.
- Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Reprint--preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Phys Ther. 2009 Sep;89(9):873-80.
- Jackson D, Riley RD. A refined method for multivariate meta-analysis and meta-regression. Stat Med. 2014 Feb 20;33(4):541-54. doi: 10.1002/sim.5957.
- Wang CL, Liang L, Fu JF, Zou CC, Hong F, Xue JZ, et al. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World J Gastroenterol. 2008;14(10):1598-602.
- Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor R, et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut. 2011;60(9):1278-83. doi: 10.1136/gut.2011.242073.
- Wojcik M, Janus D, Dolezal-Oltarzewska K, Kalicka-Kasperczyk A, Poplawska K, Drozdz D, et al. A decrease in fasting FGF19 levels is associated with the development of non-alcoholic fatty liver disease in obese adolescents. J Pediatr Endocrinol Metab. 2012;25(11-12):1089-93. doi: 10.1515/jpem-2012-0253.
- Chen S, Teoh NC, Chitturi S, Farrell GC. Coffee and non-alcoholic fatty liver disease: brewing evidence for hepatoprotection? J Gastroenterol Hepatol. 2014;29(3):435-41. doi: 10.1111/jgh.12422.
- Cynis H, Kehlen A, Haegele M, Hoffmann T, Heiser U, Fujii M, et al. Inhibition of Glutaminyl Cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice. Int J Exp Pathol. 2013 Jun;94(3):217-25. doi: 10.1111/iep.12020.
- Rodriguez A, Gena P, Mendez-Gimenez L, Rosito A, Valenti V, Rotellar F, et al. Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease. Int J Obes (Lond). 2014;38(9):1213-20. doi: 10.1038/ijo.2013.234.
- Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;12:CD008623. doi: 10.1002/14651858.CD008623.
- Kojima H, Sakurai S, Uemura M, Fukui H, Morimoto H, Tamagawa Y. Mitochondrial abnormality and oxidative stress in nonalcoholic steatohepatitis. Alcohol Clin Exp Res. 2007;S61-6.
- Xuan Zou, Chunhong Yan, Yujie Shi, Ke Cao, Jie Xu, Xun Wang et al. Mitochondrial Dysfunction in Obesity-Associated Nonalcoholic Fatty Liver Disease: The Protective Effects of Pomegranate with Its Active Component Punicalagin. Antioxid Redox Signal. 2014;21(11):1557-1570. doi: 10.1089/ars.2013.5538.
- Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, et al. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med. 1996;335(18):1357-62.
- Zou CC, Liang L, Hong F, Fu JF, Zhao ZY. Serum adiponectin, resistin levels and non-alcoholic fatty liver disease in obese children. Endocr J. 2005;52(5):519-24.
- Wong VW, Chan HL. Should all patients with nonalcoholic fatty liver disease undergo oral glucose tolerance test? J Gastroenterol Hepatol. 2011;26(3):419-20. doi: 10.1111/j.1440-1746.2010.06594.x.
- Qureshi K, Clements RH, Saeed F, Abrams GA. Comparative evaluation of whole body and hepatic insulin resistance using indices from oral glucose tolerance test in morbidly obese subjects with nonalcoholic Fatty liver disease. J Obes. 2010;2010. pii: 741521. doi: 10.1155/2010/741521.
- Suzuki A, Lindor K, St SJ, Lymp J, Mendes F, Muto A, et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol. 2005;43(6):1060-6.
- Liu WY, Lu DJ, Du XM, Sun JQ, Ge J, Wang RW, et al. Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men--the role of gut microbiota composition: study protocol for the AELC randomized controlled trial. BMC Public Health. 2014;14:48. doi: 10.1186/1471-2458-14-48.
- Mishra S, Yadav D, Gupta M, Mishra H, Sharma P. A Study of Carotid Atherosclerosis in Patients with Non-alcoholic Fatty Liver Disease. Indian J Clin Biochem. 2013;28(1):79-83. doi: 10.1007/s12291-012-0286-8.
- Chen S, Zhou H, Lin M, Mi R, Li L. Decoction vs extracts-mixed solution: effect of yiqihuoxue formula on non-alcoholic fatty liver disease in rats. J Tradit Chin Med. 2013;33(4):513-7.
- Fan JG, Cao HX. Role of diet and nutritional management in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2013;28(4):81-7. doi: 10.1111/jgh.12244.
- Alisi A, Ceccarelli S, Nobili V. Transient elastography and serum biomarkers: two-step screening methods for liver fibrosis in non-alcoholic fatty liver disease before liver biopsy. Expert Opin Med Diagn. 2012;6(5):377-80. doi: 10.1517/17530059.2012.713343.