“Traditional” liver diseases are the consequence of specific hepatic insults by agents such as viruses, alcohol, drugs, toxins, and the immune system. In contrast, nonalcoholic fatty liver disease (NAFLD; ie, fatty liver disease that occurs in the absence of significant alcohol consumption) is associated with liver injury in the context of systemic metabolic dysregulation. The latter has been operationally defined as the metabolic syndrome, with NAFLD its hepatic manifestation. NAFLD is the most common cause of liver disease in affluent nations, with a population prevalence approaching 30% [1]. In a subset of patients, nonalcoholic steatohepatitis (NASH) may supervene in the lipid-laden liver, characterized by the development of injury, inflammation, and fibrosis that can progress to cirrhosis, liver failure, and hepatocellular cancer. Furthermore, liver fat is now recognized as an independent predictor of insulin resistance, metabolic syndrome, and cardiovascular disease.
A consequence of the rapid emergence of NAFLD as a major cause of liver dysfunction has been the search for effective therapies and, in addition, the conduction of studies examining the impact of lifestyle intervention strategies to reduce liver fat. Furthermore, since NAFLD is a cofactor in other diseases including hepatitis C, alcohol-associated liver disease, and hemochromatosis, it is now apparent that lifestyle intervention should be incorporated in the routine assessment and care of most patients presenting with liver disease. This review will highlight recent information on the impact of lifestyle changes in patients with chronic liver disease with reference to diet quantity and quality and physical activity. The review will conclude with a discussion on the means to achieve sustainable lifestyle changes.
WEIGHT LOSS
The majority of lifestyle intervention studies on liver disease have been undertaken in those with NAFLD. In turn, these are predicated on the results of large trials that have examined the efficacy of lifestyle intervention in preventing type 2 diabetes and improving the metabolic risk profile of patients with impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). A summary is presented in Table 1. The source data include details of the various study interventions [2-6]. These studies have unanimously demonstrated that diet and exercise therapy reduce incident type 2 diabetes. The success of these interventions, and their relatively low dropout rate (<10%), may be partly attributable to the way in which lifestyle modification was reinforced. Common to all interventions were individual counseling, goal setting, relatively regular assessment (every 3-12 months), and multiple contacts (approximately 6-20 times per year) with staff (physician, dietitian, exercise physiologist, nurse, psychologist, or social worker). The absence of behavior change or risk reduction in the control groups of all studies, who were given lifestyle advice and information only (often 1 h of counseling), highlights the importance of intensive support but also possible difficulties of implementing lifestyle therapy in clinical practice.
 | TABLE 1. Studies of lifestyle intervention in patients with IGT |
In 1990, Palmer and Schaffner [7] reported on the effect of weight loss, achieved through moderate calorie restriction (600-800 cal/day) and physical activity in 39 overweight patients with NAFLD. At a mean follow-up of 15.9 ± 12.0 months, alanine aminotransferase (ALT) normalized in those reducing ≥10% of weight (mean weight loss 14.3 ± 3.0 kg). In 18 participants who lost <10% of initial weight, normalization of all liver enzymes occurred in 39% and ALT normalized in 63%. Liver histology was not available.
The first study to report on the histological effects of an intervention using energy restriction and exercise in liver disease (NAFLD) was by Ueno et al in 1997 [8]. It involved 15 participants over 3 months and demonstrated reductions in body mass index (BMI) from 31 ± 5 to 28 ± 4 kg/m2, improvements in aspartate aminotransferase (AST), ALT, cholesterol, and plasma glucose and a reduction in the degree of steatosis on liver biopsy. The latter correlated with improvements in other metabolic parameters such as the AST, ALT, triglycerides, and plasma glucose. While providing strong evidence for the benefits of lifestyle intervention in improving liver histology, a number of limitations preclude generalization of their results to office patients. In particular, patients were admitted to the hospital for 1 month to undergo dietary restriction and exercise therapy and then were to follow the same regime at home for 2 months. Throughout the 3 months, daily meals (equivalent to 25 cal/kg of ideal body weight) were provided. Physical activity prescription consisted of 3000 steps per day increasing to 10,000 steps per day; once this goal was attained, participants were encouraged to jog for 20 min twice a day.
Following this report, Hickman et al [9,10] reported on the effects of moderate weight loss achieved through a more practical counseling intervention in 43 patients, including 27 with chronic hepatitis C (CHC). The authors reported the results of the first 3-month intervention in participants with CHC [9] and for the total group at 15 months, after completion of a 12-month maintenance program [10]. During the 3-month intervention, participants attended weekly visits with a dietitian followed by monthly visits during the maintenance phase. Participants were counseled on energy restriction to achieve weight loss of 0.5 kg/week and to complete 150 min/week of aerobic exercise. The dietary composition recommended was 55% carbohydrate, 15% protein, and 30% fat.
In the 19 patients with CHC, a mean weight loss of 5.9 kg was reported after the initial 3-month intervention [9], with a mean reduction in waist circumference of 10.4 cm. In this group, mean ALT fell from 137 to 94 U/L over the 3 months and mean fasting insulin decreased from 16 to 11 mmol/L. In the 10 patients with paired liver biopsies, 9 demonstrated a reduction in steatosis (median reduction of 1 grade) [9]. The reduction in steatosis was correlated with the percent of weight loss; in 5 out of 9 participants who demonstrated a reduction in steatosis, a significant reduction in fibrosis was noted.
The maintenance study reported on outcomes in 31 patients among whom 21 maintained weight loss, while 32% regained weight [10]. Reductions in ALT occurred with weight loss and 11 out of 21 (52%) patients who maintained the weight loss at 15 months achieved ALT normalization. Repeat biopsies undertaken after the 3- month intervention phase in 14 patients (10 of whom were reported in the initial study) showed improvement in steatosis and fibrosis. Exercise diaries used to determine physical activity participation suggested that all but 2 participants increased their activity to at least 30 min of aerobic exercise per day after the 3-month intervention phase. The mean exercise time at 3 months was 214 min/ week, and this decreased during the maintenance phase to 120 min/week. At 15 months, exercise levels in patients who maintained weight loss were preserved at 150 min/ week. These studies in conjunction with that of Ueno et al [8] provide strong evidence (albeit in small patient cohorts) that weight loss achieved through counseling can result in improvements in liver enzymes and histology.
Huang et al implemented an intervention consisting of intense dietary counseling for 1 year in 23 patients with biopsy-proven NASH [11]. Participants were seen weekly by a dietitian for 8 weeks, biweekly for 3 months, and then monthly from 6 to 12 months and, in addition, were invited to attend 4 group sessions. Each participant received individual dietary counseling to promote weight loss of 1 to 2 lb/week and was encouraged to increase physical activity to achieve a heart rate of 70% of his or her target heart rate. Of the 23 participants commencing the study, 16 (70%) completed the intervention and 15 underwent repeat liver biopsy. At 12 months, the mean weight loss was 3.3 kg (not significant), and there were no changes in any other metabolic parameters. When the cohort was divided into those patients with an improved NASH score (n = 9) versus those with no improvement (n = 6) according to histological data, participants who achieved histological improvement had greater mean weight loss (-6.6 kg) than those who did not (+1.8 kg). A positive histological response was associated with a greater improvement in waist circumference, visceral fat, body fat, homeostasis model assessment (HOMA) score, AST, ALT, high-density lipoprotein (HDL) cholesterol, and triglyceride levels. Patients with improved liver histology also tended to have a greater reduction in carbohydrate intake, and a significant increase in their reported level of physical activity.
Several other small studies have reported improvements in liver enzymes with modest weight loss through dietary change in patients with NAFLD [11-14]. Two of these were not reporting on the effects of a dietary intervention per se, with one comparing a prescriptive diet to metformin [12], while another compared lifestyle change with or without vitamin E supplementation [13]. In the report by Bugianesi et al [12], 27 patients with NAFLD (acting as a control group) were given a prescriptive diet to achieve a calorie deficit of 500 kcal/day (weight loss of 0.5 kg/ week) for 12 months. This achieved a reduction in BMI at 12 months of 1.8 kg/m2 and normalization of ALT in 31% of participants. Notably, this result was achieved with a low-level intervention consisting of a single 2-h individual counseling session with a dietitian at baseline. In a similar vein, Okita et al reported on liver tests and anthropometry in 14 patients who undertook monthly visits with a dietitian over 6 months [14]. Patients were provided with instructions on a energy-restricted diet (25 kcal/kg of ideal body weight), encouraged to eat a diet rich in fish and green vegetables, and to use semi-skimmed or skimmed milk and dairy products. At 8 weeks, mean weight loss was 1.6 ± 0.5 kg and reached 2.4 ± 0.9 kg at week 24. ALT and AST, but not gamma-glutamyltransferase (GGT), were reduced significantly at weeks 8 and 24. Patients achieved reductions in total energy and carbohydrate intake over the 24 weeks, but there were no significant changes in fat. Notably, the ALT reduction correlated with the increase in omega 3-polyunsaturated fatty acids (PUFA) and vegetable consumption. Physical activity did not change during the study, suggesting that the results obtained were attributed to changes in diet and weight loss. It should be noted, however, that only results for patients who complied with the dietetic recommendations were included in the report.
A longitudinal study by Suzuki et al also adds evidence to the important role exercise and moderate weight loss plays in patients with NAFLD [15]. Of 348 males with elevated ALT, 136 had ALT normalization at 2 years; the factors associated with this change were commencing or maintaining regular exercise and weight loss. Furthermore, the authors noted that every 5% of weight loss was associated with a 3.6 greater likelihood of ALT normalization. Likewise, normalization of ALT was 2.5 times more likely to occur in those who participated in regular exercise (greater than or equal to once a week) than it was for those who did not [15].
In 2007, Osland et al reported on an intensive weight reduction program (weekly review for 12 weeks followed by monthly review for 12 months) for overweight patients (including those with NAFLD and CHC) attending a hospital liver outpatient clinic [16]. Of 93 referrals, 50 enrolled in the intervention, 18 received standard dietetic therapy, and 25 refused intervention. The intervention used a structured cognitive behavior therapy program designed for weight management in overweight and obese individuals. At 6 months, 83% of those enrolled in the intense intervention achieved a significant reduction in weight (mean weight loss was 4.8 ± 0.9%) and waist circumference compared to only 24% of those undertaking standard dietary intervention. The improvement in ALT correlated with a decrease in waist circumference.
A more recent study by Nobili et al in 2008 reported on the efficacy of lifestyle intervention with or without antioxidants in children with NAFLD [17]. In the lifestyle intervention group (n = 28), participants received nutritional and physical activity counseling monthly (1 h) for 24 months. At 2 years, these participants lost 4.75 kg in weight (range 4-16), together with significant histological improvements in steatosis, lobular inflammation, ballooning, and NAFLD activity score. Levels of aminotransferases, triglycerides, cholesterol, glucose, insulin, and insulin sensitivity also improved, though fibrosis was unaltered.
To date, the largest study on the effects of a behavior theory-based lifestyle intervention on the metabolic profile of patients with chronic liver disease was reported by St George et al [18]. Results of the initial intervention at 3 months have been published [18], and long-term data are awaited. In brief, the study sought to develop a practical, low-cost intervention for patients with central obesity and chronic liver disease that is applicable in usual clinical practice. In line with this approach, liver biopsies were not part of the protocol. In total, 152 participants (141 with NAFLD and 11 with CHC) with elevated liver enzymes, central obesity, and a range of metabolic risk factors were randomized to either a moderate (6 sessions for 10 weeks) or low-intensity (3 sessions for 4 weeks) lifestyle counseling intervention or to a control group. Consistent with the reports on the efficacy of lifestyle intervention in preventing the development of type 2 diabetes (Table 1) and the studies of patients with liver disease, there was an improvement in all metabolic risk factors in the moderate-intensity group, versus a smaller number of changes in the low-intensity intervention group, and no change in any risk factors in the control group. The reduction in liver enzymes was greatest in the moderateintensity intervention group and least in the controls. The likelihood of elevated ALT levels in both intervention groups was reduced by >70% compared to controls, while the proportion achieving weight loss (≥2%) was significantly higher in the moderate-intensity intervention group (66%) versus the low-intensity intervention group (39%; p <.05) and controls (29%; p = .001). While the number of patients with CHC was small, they responded in a similar fashion to those with NAFLD.
As can be seen from the publications reviewed, studies in the context of chronic liver disease have differed in the number of variables that preclude definitive statements. These include short-time frames, small participant numbers, lack of randomization to intervention and control groups, variable study design and end points, variation in the intensity and frequency of counseling and practitioner-patient contact, often intensive interventions with limited practical application, a minimal focus on physical activity, inadequate measurement of and focus on physical activity, limited data on maintenance of change over the long term, and no data on cost-effectiveness. In addition, while all studies have reported on outcomes, insufficient information and detail are provided on intervention design to allow for independent study replication. Despite these deficiencies and the inability to provide level 1 evidence like that of the diabetes prevention studies (Table 1), lifestyle interventions in participants with liver disease clearly indicate that such interventions do provide significant metabolic benefits. The studies that have reported on histological outcomes demonstrate improvements in steatosis and fibrosis that generally correlate with the extent of improvement in metabolic function, which in its broadest sense can be measured by reductions in weight, particularly central adiposity (as measured by waist circumference), and improvements in physical activity. Again, while most of the data relate to NAFLD, biochemical and/or histological improvements were noted in the small numbers of patients with CHC that have been studied.
PHYSICAL ACTIVITY
Weight loss is often perceived as the primary rationale for promoting increased physical activity and/or structured exercise training in the management of chronic liver disease. Weight loss remains fundamental to the management of NAFLD despite there being no consensus on the amount and the most appropriate rate of weight loss required to produce a hepatic benefit [19]. The reports outlined previously suggest that the synergy of aerobic exercise training and calorie restriction positively affects hepatic fat content when weight loss approximating 4 to 9% of body weight is achieved [8,10]. Large reductions (44%) in hepatic fat have also been shown following a mean 10% reduction in body weight via 6 months of energy restriction alone or combined diet and exercise therapy involving 5 days per week of aerobic exercise training [20].
Yet, it is now well established that regular aerobic exercise participation itself enhances insulin sensitivity, reduces progression to type 2 diabetes [2-6], and favorably modifies blood lipid profile [21]. When combined with the observation that habitual exercise also improves functional capacity, quality-of-life measures, and well-being and reduces all-cause mortality [22], the importance of incorporating exercise therapy, beyond its role in assisting weight loss, into the management of patients with chronic liver disease and associated comorbidities is apparent.
Exercise imparts a direct hepatic benefit in NAFLD, although the mechanism behind this remains unclear at present. Aerobic exercise substantially increases the rate of fatty acid oxidation to fuel skeletal muscle contraction, and hepatic very low-density lipoprotein (VLDL) secretion and clearance by muscle appear to increase with exercise [23]. However, fatty acids of hepatic origin may not contribute meaningfully to this elevated fat oxidation, which is widely accepted to reflect oxidation of adipose tissue and intramuscular triglyceride-derived fatty acids [24]. Rather, reduction in hepatic fatty acid infiltration, hepatic triglyceride synthesis, and increased hepatic fatty acid oxidation may explain the benefit of exercise on liver fat content. In rodent [25] and human [26] studies, regular exercise is associated with lower adipose-derived fatty acid uptake into the liver, which may reduce liver fat. Furthermore, Rector et al have shown that exercise training attenuated the development of fatty liver by increasing hepatic fatty acid oxidation and reducing de novo lipogenesis in rodent models of obesity and type 2 diabetes [27,28]. Conversely, exercise cessation in these rodents showed direct hepatic effects including a rapid increase in hepatic acetyl-coenzyme A carboxylase (ACC), reduced ACC phosphorylation, and increased malonyl-CoA and fatty acid synthase concentrations, which are known to initiate hepatic fat accumulation [27,28].
Despite growing evidence demonstrating the efficacy of lifestyle treatment targeting weight loss in chronic liver disease, the challenge is achieving sustainable weight loss through dietary and exercise intervention. Systematic reviews and meta-analyses suggest that weight loss via exercise and/or diet therapy is typically modest (1-8 kg) and returns to baseline levels within 1 to 3 years [29-31]. Thus, the relevance of exercise therapy (which confers benefits beyond weight loss) is highlighted, and there are some data to suggest that exercise participation, with or without weight loss, may be more sustainable over time [32].
The concept of “fitness versus fatness” is of growing interest, with an increasing body of data demonstrating that obese individuals can attenuate the risk of disease by being physically fit [33,34]. In the context of liver disease, despite the fact that there are clear benefits from diet and exercise therapy inducing weight loss, several reports have also implicated physical fitness and exercise therapy as an independent effector of liver fat. Cross-sectional studies show a negative relationship between liver fat and self-reported habitual physical activity levels when adjusted for body weight [35,36], although such observations need to be viewed with caution because it is well known that subjective measures of physical activity level can be inaccurate and prone to reporter bias [37]. The argument that there is a benefit of exercise participation itself in NAFLD is further supported by cross-sectional research demonstrating a negative correlation between physiological measures of cardiorespiratory fitness and NAFLD, which appear to be independent of body weight in men and women [38,39], although this is not the case in all studies [40], including lean individuals [41]. Both weight loss and self-reported regular exercise have been shown to correlate with improvement in serum ALT level during a 1-year longitudinal cohort study [15].
Intervention studies involving both diet and exercise have also shown improvement in liver fat despite relatively modest body-weight reduction. Tamura and colleagues reported that, in patients with type 2 diabetes, two weeks of combined diet and exercise therapy evoking a 3% reduction in body weight was associated with an approximately 20% reduction in hepatic fat measured by proton magnetic resonance spectroscopy (MRS) [42]. MRS is a highly reliable noninvasive technique for the quantification of hepatic triglyceride concentration [43]. In the study by Tamura et al, participants were encouraged to walk for 30 min daily 5 to 6 days per week at a moderate intensity equating with 50 to 60% of aerobic capacity; exercise adherence was confirmed by a pedometer. In a similar intervention combining diet and exercise for a longer duration (9 months), a 3% reduction in body weight was associated with a 28% mean hepatic fat reduction [44].
Recently it has been shown that in individuals who received 3 months of lifestyle counseling, those who increased their reported habitual physical activity to ≥150 min/week exhibited the greatest improvement in liver enzymes [45]. This effect was accompanied by a significant improvement in maximal aerobic capacity (the gold-standard physiological measure of cardiorespiratory fitness) and was independent of weight loss [45]. Three months of structured, supervised exercise therapy, however, was found in another study to have no measurable effect on liver fatness as inferred by computed tomography in a mixed cohort of obese and lean individuals [46], although this technique is known to be have poor sensitivity [43]. This outcome was corroborated more recently by Shojaee-Moradie and colleagues who also failed to show a significant effect from a 6-week intervention involving 3 days per week of vigorous intensity cycle training on MRS-measured liver fat content, although abdominal visceral adiposity was reduced. However, the participants in this investigation were overweight but did not have NAFLD [47]. In contrast to these latter studies, a short-term (4 week) aerobic exercise intervention showed that both liver fat content and visceral adiposity can be reduced without any associated change in body weight in obese and previously sedentary individuals with NAFLD [48]. In this investigation, participants allocated to a progressive aerobic exercise program involving 30 to 45 min of cycling 3 days per week were graduated from moderate to more vigorous intensity (50 to 70% of aerobic capacity) over 4 weeks and experienced a mean 21% reduction in MRS-measured liver fat. This occurred despite no loss of abdominal subcutaneous fat or body weight. All exercise was supervised by an exercise physiologist. While further research is required to demonstrate the long-term efficacy of this therapy, this study provides important evidence that exercise imparts a direct hepatic benefit in individuals with NAFLD that is independent of that achieved by weight loss. Thus, while weight loss should remain a fundamental goal in the management of NAFLD, patients should be counseled on the spectrum of benefits associated with regular exercise and assisted in setting lifestyle goals that are based on exercise dose rather than weight loss outcomes per se.
The dose (intensity and volume) of exercise required to prevent hepatic steatosis, lower liver fat, and improve liver function remains unclear. Furthermore, from available evidence it is difficult to discern the relative importance of “cardiorespiratory” fitness (maximal aerobic power) and physical activity level. In the absence of such data it seems reasonable to promote the current public health recommendations, which suggest that healthy individuals should accumulate 30 min or more of moderate-intensity physical activity on most days of the week, performed continuously or as intermittent bouts throughout the day [22]. However, it is widely accepted that these guidelines (approximately 150 min/week of exercise) do not lead to significant weight loss or prevent weight regain long term [49]. This has led to guidelines targeting 80 to 90 min of daily physical activity when aimed at body weight management, which equates with an energy equivalent of approximately 1200 to 2000 kcal/week [49]. It should be emphasized that the actual reduction of weight (and body fat) with this dose of regular exercise in overweight and obese individuals is typically still small (approximately 2-3 kg), but increases (approximately 5-7.5 kg) with physical activity levels between 225 to 420 min/week [29,31,49].
The major lifestyle intervention studies have shown that 150 to 280 min/week of structured exercise and increased incidental activity, delivered in isolation or in combination with diet therapy or metformin, is effective in improving secondary outcomes including insulin sensitivity, dyslipidemia, blood pressure, and incident metabolic syndrome [2-6]. Exercise therapy in these studies used a variety of modalities, including brisk walking, jogging, cycling, swimming, dancing, skiing, ball games, or equivalent sporting activities, with occupational activity included in physical activity goals in some [2,5] but not others [4,6]. Lifestyle strategies for increasing physical activity such as the use of stairs rather than escalators, gardening, housework, and yoga were not included toward physical activity goals in most studies, and progressive resistance training was also incorporated in the Diabetes Prevention Program and Finnish interventions [2,6]. It is notable that the decreased risk of diabetes was correlated with weight loss in these investigations, but exercise adherence also significantly reduced this risk independent of weight loss [2,6]. Although there is currently no evidence available concerning its benefit in NAFLD, progressive resistance training may also be useful for the management of obesity-related comorbidities, particularly insulin resistance [50].
A major consideration for lifestyle therapy is that adherence to diet and exercise intervention can be poor in a clinical setting [2-6]. In light of the lack of data regarding lifestyle intervention in the specific management of chronic liver disease, the diabetes prevention studies provide important insights regarding behavior therapy to target exercise adherence. While different behavioral approaches were used, the intervention arms in all studies included behavioral strategies for reinforcing prescribed changes in physical activity, dietary intake, or the combination, and included initial lifestyle counseling sessions and ongoing regular contact, self-selection of goals and physical activity strategies, and recording of participation, which are known to enhance adherence to exercise programs [51]. Recent technological advances have enabled relatively inexpensive objective quantification of physical activity to be achieved, including accelerometers and pedometers, which may further promote physical activity and exercise adherence by increasing physical activity awareness and providing feedback and motivation [52]. Although pedometers are poor predictors of the metabolic strain of exercise, in the absence of direct evidence concerning effects of exercise intensity on NAFLD management, 1000 steps for 10 min of exercise appears to elicit an exercise intensity that is compatible with that prescribed by current guidelines [53].
SUMMARY AND RECOMMENDATIONS
Lifestyle intervention is clearly an important component of the management of patients with chronic liver disease when it is associated with excess liver fat deposition and other features of the metabolic syndrome. Such intervention significantly increases the likelihood of positively impacting liver histology. The key question is to define what does and does not work in typical office practice. In this regard, an ideal scenario would include government and policy initiatives to improve diet quality and quantity and a redesign of urban environments and individual strategies managed at the level of the primary care physician and specialist. An integrated lifestyle management unit comprising physicians, dietitians, exercise physiologists, and psychologists is likely to be the gold standard, but for the vast majority is unattainable due to resources and a variety of other logistic issues. For the remainder, therefore, individual strategies need to be developed. In the majority, a behavior theory based approach is likely to provide the best long-term outcomes. Data from the diabetes prevention programs demonstrate that intervention that focuses only on the provision of advice and information has little effect on promoting sustainable behavior change. Rather, lifestyle therapy should be viewed as a process involving both practitioner and patient that focuses, particularly in the early phases, on diet and exercise education, the use of individualized goals and approaches, with self-monitoring and regular follow-up and assessment.
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