The effects of diet and lifestyle interventions on insulin resistance in patients with nonalcoholic fatty liver disease: a systematic review
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Paris, Tonyaa; George, Elena S.a,b; Roberts, Stuart K.c; Tierney, Audrey C.a,b
European Journal of Gastroenterology & Hepatology Aug 2017
"Insulin Resistance - IR is a pathogenic factor underlying the progression of NAFLD.
It correlates with enhanced oxidative stress and histopathological disease severity of NAFLD correlates significantly with oxidative stress parameters 39. Assessment of positive improvements with diet and lifestyle interventions on IR is a first step or basis for preventing further complications of NAFLD progression.
Diet and diet and exercise resulting in weight loss significantly improves IR in patients with metabolic syndrome. All diet and diet and lifestyle intervention trials were efficient in reducing IR in participants with NAFLD....monitoring IR could potentially be a noninvasive way to assess the severity of NAFLD advancement and monitor the effectiveness of diet and diet and lifestyle interventions in this patient group
The effect of weight loss as a result of these interventions is consistent with other systematic reviews that have investigated the effect of diet and lifestyle modifications on liver specific outcome measures in NAFLD and showed an improvement with the overall
NAFLD disease severity
These studies focused on outcome measures such as histological and biochemical improvements (intrahepatic triacyglycerol concentration, and/or liver aminotransferases, glucose control and insulin sensitivity) and improvements in radiological steatosis. Although changes in liver-specific outcomes were not the focus of this review, it was evident from the studies included that the interventions used had significant favourable effects on steatosis 35,38, liver enzymes 31,32,34,36-38, liver grading 33 and disease activity of NASH 38 compared with control groups, with the majority attributable to the weight loss achieved."
Nonalcoholic fatty liver disease (NAFLD) results from excessive fat accumulation in the liver in the absence of excessive alcohol consumption. Insulin resistance (IR) is proposed to be an underlying pathogenic factor in the development and progression of disease. There are currently no proven pharmacotherapies and weight loss is the only prescribed treatment despite a lack of evidence to support a specific diet or lifestyle therapy. The aim of this review is to evaluate the efficacy of dietary lifestyle interventions on IR measured by Homeostasis model assessment in patients with NAFLD. A systematic electronic search of Medline, Scopus, The Cochrane Library, CINAHL and PubMed databases (1999-2015) was performed by two independent reviewers. Randomized control trials evaluating the efficacy of diet and lifestyle interventions on IR in adults diagnosed with NAFLD were included. A total of 6441 articles were identified; eight randomized control trials fulfilled the inclusion criteria. Three studies involved dietary interventions and five incorporated diet and exercise. The majority of intervention groups resulted in significant reductions in IR, with no significant changes observed in the control groups. Lifestyle interventions compared with controls reduced IR measured by homeostasis model assessment. All diet and diet and lifestyle intervention trials were efficient in reducing IR in participants with NAFLD. A lack of literature and variation across interventions warrants the need for extensive research to establish firm dietary lifestyle recommendations.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, affecting ∼20-30% of adults in developed countries, with the prevalence increasing to 75% in obesity and 50-75% in those with type 2 diabetes (T2DM) 1-6. The disease is defined as an accumulation of excess fat in the form of triglycerides in liver cells that occurs in the absence of excess alcohol consumption (>20 g/day) 7,8. The disease progresses from simple steatosis to nonalcoholic steatohepatitis (NASH), where excess fat stores are associated with inflammation of the liver. This may progress to the development of liver fibrosis and cirrhosis with disruption to liver architecture and function 9,10. Insulin resistance (IR) is a common pathogenic factor underlying the progression of NAFLD 11. Epidemiological studies show a high prevalence of NAFLD in conditions associated with IR, such as abdominal obesity, T2DM, dyslipidaemia and the metabolic syndrome 12-14. Indeed, NAFLD has been considered the hepatic manifestation of the metabolic syndrome. The pathogenesis of NAFLD and NASH is incompletely understood and complex. One popular theory is that 'two hits' are involved 15. The first 'hit' involves the development of hepatic steatosis (fatty liver), with IR being a major risk factor in the net retention of lipids within hepatic liver cells 16-18. The second 'hit' is the progression of steatosis to NASH and fibrosis/cirrhosis and involves inflammatory mechanisms. Although these proposed theories have not been adequately defined, it is believed that diminished mitochondrial β-oxidation leads to decreased clearance of fatty acids 17.
IR is a disorder characterized by reduced responsiveness of peripheral tissues to the action of insulin secreted by pancreatic β-cells leading to relative hyperglycaemia and T2DM 19. The euglycaemic clamp is the gold-standard technique for the measurement of IR; however, because of its impracticality, labour and duration, it is limited in its application in medical practice and clinical trials 20. A number of surrogate methods have therefore been used to simplify and improve the determination of IR 21. The homeostatic model assessment of insulin resistance (HOMA-IR) is an index that measures the functioning of beta cells releasing insulin by using a calculation of fasting glucose and insulin concentration levels in the blood 22. HOMA-IR has proven to be a popular and efficient tool used to measure IR in many published clinical trials because of simplicity in its calculation 23. HOMA-IR and the euglycaemic clamp have been compared and similar values for IR have been found 22.
The current literature suggests that dietary modifications resulting in weight loss are more effective than pharmacotherapies in the treatment of NAFLD 24,25. Diet and diet and exercise resulting in weight loss significantly improves IR in patients with metabolic syndrome 26. With NAFLD becoming more prevalent and in the absence of meaningful therapy, monitoring IR could potentially be a noninvasive way to assess the severity of NAFLD advancement and monitor the effectiveness of diet and diet and lifestyle interventions in this patient group. To the author's knowledge, a systematic review investigating the effect of diet on IR as an outcome measure in NAFLD is yet to be performed. Therefore, the aim of this systematic review is to determine the effect of diet only and diet and lifestyle interventions on IR as measured by HOMA-IR in patients with diagnosed NAFLD.
A systematic search of the electronic databases Medline, CINAHL, Scopus, PubMed and The Cochrane Library was performed in April 2015 and eligible studies were identified by the primary author. Limits were applied for the year of published articles (1999-2015) and language (English). If full-text articles were not available in English or if articles could not be retrieved, authors were contacted. An eligibility assessment of the articles was performed independently by two reviewers. Disagreements between reviewers were resolved by a third reviewer. Two reviewers also viewed search terms and article extraction data to ensure that they were correctly selected against inclusion and exclusion criteria.
The following selected key search terms were used in all database searches including MEDLINE with truncations and MESH terms: ('NAFLD' or 'NASH' or 'fatty liver' or 'liver disease' or 'non-alcoholic fatty liver' or 'nonalcoholic fatty liver' or 'non-alcoholic steatosis' or 'nonalcoholic steatosis' or 'steatosis') AND ('nutrition counseling' or 'calorie restrict*' or 'lifestyle' or 'weight reduction' or 'weight loss' or 'dietary intake' or 'high carbohydrates' or 'low carbohydrates' or 'CHO' or 'low fat' or 'high fat' or 'saturated fat' or 'monounsaturated fat' or 'polyunsaturated fat' or 'PUFA' or 'MUFA' or 'diet*' or 'Mediterranean diet') AND ('Insulin resistance' or 'HOMA-IR' or 'metabolic syndrome' or 'fasting glucose' or 'insulin sensitivity' or 'hyperinsuline*' or 'euglyce*' or 'oral glucose').
The review was restricted to published prospective interventions reporting the effects of diet and/or lifestyle modification on IR in participants with NAFLD/NASH/steatosis.
Types of studies
Randomized-controlled trials (RCTs) were selected for this review. Reviews, letters, editorials, commentaries, animal studies and duplicate articles were excluded. In addition, pilot studies, prospective cohort studies, nonrandomized interventions, case-control, cross sectional and case series were later excluded as these study designs did not compare the effects of a control and an intervention group. Full reports with sufficient information published in English were included to allow for the critical evaluation of the effects of the intervention on HOMA-IR in NAFLD.
Studies with participants diagnosed with NAFLD and older than 18 years of age were included. Articles were excluded if participants had liver diseases such as cirrhosis or hepatocellular carcinoma, conditions caused by excessive alcohol consumption and comorbidities without the presence of a diagnosis of NAFLD. It was considered sufficient if authors provided their own valid and justified diagnostic criteria for NAFLD or NASH. Diagnoses made with either histological examination of biopsies, proton magnetic resonance spectroscopy, computed tomography ultrasound and/or blood concentrations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) were included.
Types of interventions
Dietary interventions alone and those that included diet as well as lifestyle interventions were included. Lifestyle interventions encompassed general lifestyle counselling by dietitians and/or the prescription of exercise. Diet and lifestyle interventions that incorporated nutritional supplements and/or pharmaceuticals were excluded. Studies focusing on supplements and/or pharmaceuticals alone were excluded. Exercise-only interventions were also excluded from this review.
Types of outcome measures
The primary metabolic outcome measure of interest was a reduction in IR measured using the HOMA-IR equation.
Articles were first excluded on the basis of title and abstract against inclusion and exclusion criteria. Studies that appeared eligible on the basis of their abstracts were obtained and full texts were read and assessed.
Data extraction and data items
Data extraction was carried out on the articles included in the systematic review. The information extracted from each trial included the following: (a) participants' characteristics (including the number of participants in the study, age, BMI, sex and the demographic location of the study); (b) the duration of the intervention and details of what the intervention and control groups were required to undertake (including the type of diet plan and exercise, frequency of physical activity, duration and intensity, nutritional intervention, dietary assessments); and (c) the methods used to record the diagnosis of NAFLD.
Risk of bias and study methodological quality assessment
The American Dietetic Association quality criteria checklist was used to assess the risk of bias and the studies' overall quality rating. Key questions address whether or not the selection of participants are free from bias, whether the groups were comparable, whether the intervention regimes were described in detail and whether the outcomes were clearly defined and the measurements are valid and reliable. Positive scores obtain a yes answer for the questions addressed.
A meta-analysis was not carried out for studies in this review. This review is descriptive in nature. This review followed the PRISMA guidelines for reporting of systematic reviews 27.
Study selection process
The initial search of the selected databases retrieved a total of 6441 citations. After excluding duplicates, a total of 5330 articles remained. Furthermore, 5170 were excluded as articles were reviews, animal interventions or cell studies, leaving 160 full-text articles to be assessed for eligibility. One hundred and fifty-two articles were excluded as the study population were not NAFLD participants, IR was not an outcome measure, articles were not in English, studies were not RCTs and/or diet and lifestyle interventions had nutritional and/or pharmaceutical supplementations. For full-text articles that were not available, authors were contacted. However, no replies were received and as such, these articles were then excluded 28-30. A total of eight RCT were identified for inclusion in this review (Fig. 1).
The risk of bias and study methodology quality assessment scores
Two studies included in this systematic review received an overall neutral quality assessment rating 31,32. This was because of the uncertainty as to whether or not the selection of the sample was free from bias and whether the participants were blinded to their group allocation. Six of the articles received a positive score in the quality assessment tool 33-38. One study reported a limitation in that participants in the intervention group could make their own food choices and reported their own consumption of foods 33. There was a lack of information on diet observations, physical activity measurement, a lack of follow-up and details on behavior change in two studies 31,34. The duration of the intervention in two studies was perceived as inadequate 35,36. Three studies did not measure the severity of histological liver injury 31,32,37. In addition, various measures and diagnostic techniques were used for fatty liver assessment across the studies. One study had a small sample size and two studies only considered men (Table 1) 33-35.
Study findings - effects on homeostatic model assessment of insulin resistance diet-only interventions
Three of the eight studies included focused solely on dietary interventions for the improvement of HOMA-IR in patients with NAFLD 31,33,35 (Table 2 and Table 4). There were a total of 267 participants across the three studies, with an equal number of men and women. The age of the participants ranged between 37 and 55 years, with a BMI range of 27-38 kg/m2. A variety of methods were used to diagnose NAFLD across the three studies including elevated ALT 31, liver biopsy 35 and ultrasonography 33. The duration of the interventions ranged from 1.5 to 6 months. The prescribed diets within the intervention and control groups varied among the studies. The study by Nigam et al. 33 consisted of an intervention group consuming 20 g of olive oil, an intervention group consuming 20 g of canola oil and a control group consuming 20 g of soyabean oil. A 45-min brisk walk was recommended, but was not mandatory throughout the 6-month intervention. Similar improvements in IR were observed with canola (reduction of HOMA-IR score of 1.3, P=0.001) and olive oil (reduction of HOMA-IR score of 1.5, P=0.001) compared with the control group (reduction of HOMA-IR of 0.2, P>0.05). Ryan et al. 35 conducted a randomized cross-over trial with a Mediterranean diet (MedD) intervention group and a low-fat/high-carbohydrate (CHO) diet control group. Each participant consumed both diets for 6 weeks, with a 6-week washout period. The MedD group showed significantly improved IR (reduction in HOMA-IR of 1.7, P<0.01) compared with the low-fat/high-CHO diet (reduction in HOMA-IR of 0.2, P<0.05). De Luis et al. 31 investigated the effects of two diets: a hypocaloric low-fat and a hypocaloric low-CHO diet. It was found that both diets were effective in improving IR; however, the low-fat diet showed greater improvements (reduction in HOMA-IR of 9, P<0.05) compared with the low-CHO diet (reduction in HOMA-IR of 3.9, P<0.05). Although all studies assessed IR, the primary outcome of each study varied. They involved either reducing the severity of liver steatosis, reducing body weight and decreasing liver enzymes 31,33,35. The various dietary interventions resulted in significant reductions in HOMA-IR compared with control groups. An average reduction in HOMA-IR scores of 1.5-9 was observed across these studies. No significant differences were observed between preintervention and postintervention for the control groups, with a reduction in the overall HOMA-IR score ranging between 0.2 and 3.9. Overall, the study by De Luis et al. 31showed that a hypocaloric low-fat diet led to the greatest significant reduction in IR. In this study, both diet groups lost on average 4 kg in weight. In the study by Nigam et al. 33, participants who consumed olive oil achieved the greatest average weight reduction of 5 kg, those who consumed canola oil achieved an average weight loss of 4.2 kg, whereas the control group lost an average 1.6 kg. In the study by Ryan et al. 35, participants who consumed the MedD lost 1 kg in weight, albeit nonsignificant. Those who consumed the low-fat/high-CHO diet lost on average 2.4kg of weight.
Diet, exercise and counselling interventions
Five of the eight articles in this systematic review consisted of interventions that incorporated diet and exercise regimes (Table 3 and Table 4) 32,34,36-38. There were a total of 1595 participants; the age of the participants ranged between 35 and 55 years and BMI ranged between 31 and 38 kg/m2 across the studies. The study duration ranged from 2.5 to 12 months. The diagnosis of NAFLD was made by biopsy 38, high liver enzymes 32,34,37 and/or by ultrasonography 36. The dietary interventions differed in macronutrient compositions, achieving either a general restrictive hypocaloric diet 34,37,38, a diet tailored to the individual's requirements (moderate CHO, protein and fats) 38, high in monounsaturated 34 or high polyunsaturated fat 32. Exercise interventions involved jogging, walking, stair climbing, step tracking, cycling and/or strength training or a combination, ranging from three times per week to everyday for 20-60 min 32,34,38. In two studies, participants were randomized in a 2 : 1 ratio to a lifestyle intervention or a control group 36,38. The intervention group involved a tailored diet tailored on the basis of the individual's requirements (based on a fat-reduced and sugar-reduced diet) and increased physical exercise 36. The control group received education on NAFLD and principles of healthy eating, physical activity and weight control 38. The intervention group received a calorie goal on the basis of their starting weight (1000-1200 kcal/day if baseline weight was <200 lb or 1200-1500/day if baseline weight >200 lb) and a daily fat gram goal designed to meet 25% energy from fat (28-33 g for 1000-1200 kcal diet or 33-42 g for the 1200-1500 kcal diet) and moderate-intensity physical activity 38. The control groups either attended nutrition classes, which provided information on health, lifestyle and education about NAFLD 36, or no treatment 38. A study by Aller et al. 32 applied a hypocaloric diet high in monounsaturated fat in one group and a hypocaloric diet high in polyunsaturated fat in the other group. In the study by Al-Jiffri et al. 34, the participants in the intervention group followed a low-calorie diet with on average 15% energy as protein, 30-35% as fat and 50-55% as CHO to provide about 1200 kcal daily with aerobic exercise. Participants in each intervention group showed significant improvements in IR, varying from a reduction in the HOMA-IR score between 0.2 and 2. The control groups in each study showed little improvements or an increase in the HOMA-IR score. The score varied between -1.07 and +0.47. Although the primary goal in these studies was to improve metabolic outcomes that were associated with NAFLD, these lifestyle interventions aimed at achieving a reduction in body fat percentage by incorporating exercise as well as diet. The diet and lifestyle intervention that showed the greatest reduction in IR was a 1000-1200 kcal/day diet if baseline weight less than 200 lb or 1200-1500/day if baseline weight more than 200 lb and a daily fat gram goal of 25% total energy 38. They incorporated an exercise regime involving either 10 000 steps/day, cycling, aerobic dance or strength training 38. These intervention studies showed an overall positive effect in lowering the levels of IR in participants with NAFLD. In the study by Al-Jiffri et al. 34, there was a 15% average weight loss reduction in the intervention group, with a reduction in HOMA-IR of 1.35. The study by Aller et al. 32 showed a greater weight reduction in participants who consumed the diet high in monounsaturated fat (-4.9 kg), whereas those who consumed a diet high in polyunsaturated fat lost an average 1.7 kg. However, a greater reduction in HOMA-IR was observed in the polyunsaturated fat diet group (-1.07) compared with the monounsaturated fat group (-0.80). The study by Promrat et al. 38 showed an average weight loss of 8.7 kg and a reduction in HOMA-IR of 2 U in the intervention group and a weight loss of 0.5 kg and an increase of 0.1 in HOMA-IR in the control group. In the study by St George et al. 37, an average weight loss of 3.8 kg was observed in the intervention groups with six fortnightly consultations and 1.9 and 0.5 kg in the low-intensity group with three fortnightly consultations and the control group with an initial consultation to interpret the patients' results, respectively. The consultations involved dietetic counselling on recommendations of healthy eating and exercise 37. IR improved marginally in the intervention group (-0.4), with no change in the control group. There was an average weight loss of 6.1 kg in the intervention group and an average weight gain of 1.3 kg in the control group in the study by Sun et al. 36 IR improved by a reduction in HOMA-IR of 1.54 U in the intervention group in this study.
The authors did not carry out a meta-analysis because of the total number of cases being small, wherein a single study would have accounted for 99% of the total weight 36; most studies were of low quality, interventions differed in terms of diet and physical activity and/or behavioural therapy and the duration of treatment varied between 3 and 12 months.
IR is strongly implicated in the pathogenesis and progression of NAFLD and NASH and one of the major metabolic factors associated with the metabolic syndrome 39. In addition, it is considered to be a key cofactor associated with the progression of other liver diseases, particularly hepatitis C. Hence, there are significant implications in relation to liver disease by evaluating dietary therapy to improve IR. This systematic literature review examined the effects of diet alone or in combination with a lifestyle intervention on IR as measured by HOMA-IR in patients with diagnosed NAFLD. Interventions with diet modifications only showed significant reductions in HOMA-IR compared with control groups. Diet and exercise interventions were also effective in reducing HOMA-IR up to two units in patients with NAFLD. Diet and lifestyle interventions that applied energy restrictions and resulted in weight reduction were the most frequently used and proved effective in reducing IR in overweight and obese NAFLD patients. It remains unclear which diet and lifestyle regime had the greatest effect in lowering IR in participants with NAFLD.
The effect of weight loss as a result of these interventions is consistent with other systematic reviews that have investigated the effect of diet and lifestyle modifications on liver specific outcome measures in NAFLD and showed an improvement with the overall NAFLD disease severity 40-42. These studies focused on outcome measures such as histological and biochemical improvements (intrahepatic triacyglycerol concentration, and/or liver aminotransferases, glucose control and insulin sensitivity) and improvements in radiological steatosis. Although changes in liver-specific outcomes were not the focus of this review, it was evident from the studies included that the interventions used had significant favourable effects on steatosis 35,38, liver enzymes 31,32,34,36-38, liver grading 33 and disease activity of NASH 38 compared with control groups, with the majority attributable to the weight loss achieved.
In addition to the overall effect of weight loss, it is important to acknowledge that other covariates including ethnicity, age, sex distribution and baseline BMI values could play a contributory role in the link between the effect of diet and IR. The internal heterogeneity across the trials makes it difficult to objectify their role.
IR is a pathogenic factor underlying the progression of NAFLD 11. It correlates with enhanced oxidative stress and histopathological disease severity of NAFLD correlates significantly with oxidative stress parameters 39. Assessment of positive improvements with diet and lifestyle interventions on IR is a first step or basis for preventing further complications of NAFLD progression. In previous systematic reviews 40-42, not all studies reported on IR. They also encompassed a wide range of study interventions, such as exercise only, interventions combining diet and specific or broad physical activity/exercise advice and interventions incorporating lifestyle interventions with pharmaceuticals/supplementation such as insulin sensitizers, lipid-lowering drugs and antioxidants 40-42. HOMA-IR is used to measure IR in many published clinical trials because of simplicity in its calculation 23. HOMA-IR and the euglycaemic clamp have been compared and similar values for IR have been determined 22. HOMA-IR can be measured more easily to guide clinicians in their management. Liver-specific outcomes are not always easily obtained (especially paired biopsies) and LFTs can be an unreliable outcome measure with respect to the effect of dietary change.
The majority of studies in this systematic review aimed to reduce IR through the application of diet and exercise to achieve weight loss. From this review, it was observed that body weight reductions between 4 and 15% were found to be a potential therapeutic target in lowering HOMA-IR. Elias et al. 43 reported that a recommended weight loss of 5% of initial body weight is an effective way to reduce risk factors in the treatment of NAFLD. Weight loss has a significant impact in reducing IR and other related metabolic health outcomes such as an improvement of liver enzymes, weight, cholesterol levels and steatosis. The improvement in metabolic outcomes seems to be related to the amount of weight reduction 44.
There are a number of associated dietary factors that increase the development of fatty liver disease such as high intakes of refined CHOs and saturated fat 45. There are a growing number of dietary intervention trials aiming to reverse these negative dietary habits 46. Emerging evidence has suggested that a traditional MedD high in monounsaturated fatty acids could be an effective treatment as it has been found to reduce steatosis and IR in NAFLD and improve a cluster of metabolic risk factors 35,47,48. In practice, when recommending a healthy dietary pattern for adults with NAFLD, adhering to a MedD is a good alternative to a western diet, wherein it is associated with an improvement in overall health status, a reduction in overall incidence mortality and mortality from cardiovascular disease 49.
It is complex to separate the beneficial effects of diet and exercise alone in clinical trials. Research papers focusing purely on exercise interventions in NAFLD were not included in this review. Currently, there is a lack of consistent and robust evidence to suggest that exercise alone improves IR, hepatic fat and inflammation 50. Two studies reported that aerobic exercise does improve visceral lipids and serum aminotransferases, with no significant change in HOMA-IR in obese NAFLD patients 51,52.
The variety of diets and exercise patterns reported throughout this review makes it difficult to determine which interventions result in the greatest reductions in IR (Table 4). There is also conflicting evidence around whether diet and exercise independent of weight loss improves IR. The variety and lack of consistency among intervention prescription has also been noted in other studies that investigated different diet and exercise regimes on populations at risk of NAFLD such as participants with obesity, T2DM and metabolic syndrome (Table 4) 53. Although improvements in IR were observed in NAFLD patients, the lack of consistent literature, duration and sustainability of appropriate diet and exercise lifestyle interventions limits translation into clinical practice. More robust and consistent high-quality research in this participant group is required to develop firmer dietary and lifestyle recommendations.
In this systematic review, studies used a number of different methods to diagnose NAFLD including the less invasive albeit less sensitive and precise method of measuring serum liver enzyme aminotransferases 40. It has been shown that serum aminotransferase levels may be normal in patients with histologically proven NAFLD, wherein 10% of NASH patients have normal ALT and AST levels 54. ALT alone is not a reliable diagnostic measure for clinical settings and interventional trials 49. However, despite the lack of correlation with histological liver injury and liver enzymes, they can serve as an early indication of NAFLD before the definitive diagnosis of a liver biopsy and thus we believed were important to include in their assessment of response to diet and lifestyle interventions. Given the findings, it was decided by the authors to include studies that diagnosed NAFLD with liver enzymes as they also had large study populations and the effect of diet and lifestyle interventions on IR was noteworthy. We acknowledge that the use of liver enzymes to diagnose NAFLD is flawed; however, in the absence of noninvasive diagnostic tools for this population, they are easily measured and accessible and capture larger population data.
The limitations of this systematic review need to be acknowledged. Notably, among 6641 articles potentially identified for review, only eight studies were selected. The total number of cases was relatively small and one study 36 accounted for over 50% of total cases. The small number of studies included in this review is because of the inclusion criteria, which specifically screened for RCTs of diet alone or alongside lifestyle interventions. Observational studies that are well designed and carried out are useful in alluding to cause and effect relationships, however, were excluded from this review. There were a number of different interventions and the duration of these interventions varied (between 6 weeks and 12 months) across each of the articles; this inconsistency made it difficult to determine which intervention had the greatest impact on IR. Follow-up durations among the studies were also inconsistent.
The outcome measure in this systematic review was HOMA-IR, a surrogate marker of IR. The limitation of this surrogate measure needs to be acknowledged; it is not the gold standard and its clinical significance has been questioned. Using HOMA-IR as a way to monitor the disease progression of NAFLD has been debated in European guidelines; however, it is accepted in patients without diabetes. However, HOMA-IR is quick and inexpensive to carry out in a clinical setting and does not require increased labour resources. It can provide a good indication of disease progression alongside other clinical and biochemical markers. Given its flaws, it continues to be used widely in research and clinical-based studies. An improvement in HOMA-IR during weight loss may indicate metabolic improvement that is beneficial for NAFLD 55.
In terms of the quality of the studies in the review, two out of the eight articles included were assigned a neutral score on the basis of the American Dietetic Association quality-rating tool assessing the methodology of study designs because of the uncertainty as to whether or not the selection of the sample was free of bias. The other studies, although deemed positive, had some inherent biases within. Some of the full-text articles could not be retrieved from authors when contacted and it is unknown whether these findings would have altered the outcomes of this review. There was variability and no set criteria for the diagnosis of NAFLD, which is a limitation because of the inconsistencies between disease severity, diagnosis of participants and discrepancies among the interpretation of the results of the study included in this review.
Diet and lifestyle programmes are often difficult to adhere to and full-time counselling including prescriptive advice may not be obtained. Weight loss can be difficult to maintain and many patients re-establish their baseline weight. These studies did not investigate the long-term outcomes and therefore we cannot determine whether these improvements, that is, reduction in IR are sustainable. There is a lack of robust RCTs published with a definitive histological diagnosis investigating metabolic outcomes such as IR. More extensive trials are needed to establish whether these interventions can be effective in treating NAFLD in the long term 56,57. In addition, the mechanisms behind the benefits of hypocaloric diets and exercise on IR have not been well investigated; therefore, more physiological research is needed 58,59.
Despite these limitations, these findings are clinically important. The collective reductions in HOMA-IR observed are significant for the NAFLD population, given that IR is the underlying insult in the development and progression of the disease. Diets with and without lifestyle interventions were shown to be effective, which is essential in the absence of an effective therapy in a highly prevalent condition. IR, the underlying mechanism of NAFLD, which is related to a number of other chronic diseases, improved with the variety of interventions. However, further studies need to be carried out to determine the most effective and sustainable diet intervention.
The effects of diet and exercise on IR in NAFLD were evident only in overweight and obese populations with the disease. Improvements in diet and exercise can ameliorate IR in this population. It would seem that weight loss in this group is a significant driver in achieving a reduction in HOMA-IR as well as in improving liver-specific markers and the overall metabolic profile. For both normal-weight, overweight and obese patients with NAFLD, the type of intervention and specifically the composition of the diet or diet and exercise combination most effective in achieving overall metabolic benefits still needs to be elucidated. With weight loss maintenance unsupported by the literature, an intervention that can achieve better health outcomes without weight loss could potentially be superior and more sustainable in the future.