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National Guideline Centre (UK). Non-Alcoholic Fatty Liver Disease: Assessment and Management. London: National Institute for Health and Care Excellence (NICE); 2016 Jul. (NICE Guideline, No. 49.)
11.1. Introduction
Given both the absence of any pharmacological interventions specifically licensed at present for the treatment of NAFLD – as well as concerns about the difficulties in complying with lifestyle interventions – there is great interest in alternative therapeutic strategies for the condition. One such strategy focuses on dietary modifications or supplements, with a number of different interventions that have a robust scientific rationale for being of potential clinical benefit having now been evaluated in clinical trials. This review question sought to review the clinical and cost-effectiveness of these dietary interventions.
These interventions take a number of different forms:
- Omega-3 fatty acids: Typical Western diets are associated with a significant increase in the ratio of omega-6 fatty acid consumption compared to omega-3 fatty acids. The potential consequences of this include impaired regulation of hepatic and adipose function (predisposing to hepatic fat deposition) as well as increased production of pro-inflammatory arachidonic acid-derived eicosanoids (which may predispose to steatohepatitis). Given that omega-3 fatty acid supplementation is well-recognised to improve both hypertriglyceridaemia and insulin sensitivity (as well as conveying systemic anti-inflammatory effects), it has been proposed that omega-3 fatty acid supplementation may slow down or even reverse hepatic steatosis and steatohepatitis.
- Probiotics and prebiotics: People with NAFLD appear to have an alteration in the composition of their gut microbiota and increased intestinal permeability in comparison to healthy people without the condition. Whether this acts as a cause of NAFLD, consequence or is purely incidental remains unclear; however, there is increasing evidence for interaction between the gut microbiota and the host metabolism, as well as recognition that a consequence of intestinal permeability may be increased exposure of the liver to potentially pro-inflammatory gut-derived microbial products. Together, this suggests that the gut-liver axis may directly influence the onset and progression of NAFLD. By extension, it has been proposed that modulation of the gut microbiota (by means including probiotics (defined as live micro-organisms that are proposed to convey a health benefit to the host when ingested) or prebiotics (non-digestible food components that promote the growth or activity of micro-organisms within the gut that may convey a health benefit to the host) may slow down or reverse hepatic fat deposition and steatohepatitis.
Other dietary modifications that may also influence the onset and progression of NAFLD (including caffeine, alcohol and fructose) are evaluated in separate review questions within this guideline.
11.2. Review question: What is the clinical and cost-effectiveness of dietary modifications or supplements for adults, young people and children with NAFLD compared with standard care?
For full details see review protocol in Appendix A.
Table 50
PICO characteristics of review question.
11.3. Clinical evidence
Twelve studies were identified that were relevant to the review protocol (1 study is reported in 2 separate papers).9,10,14,46,74,128,133,159,165,166,179,198,217 Three RCTs assessed probiotics in adults,10,46,217 and 2 in children. 9,198 Four studies assessed omega-3 fatty acids in adults.14,159,165,166,179 and 3 in children.74,128,133 The diagnostic tests used to identify participants with NAFLD varied between the studies (Table 51).
Table 51
Summary of studies included in the review.
Only 1 of the papers identified for omega 3 fatty acids in children provided information in the format that could be quality assessed using GRADE. The remaining evidence was provided in graphical format in 1 paper, and median and IQR for another. Therefore, in order to include more evidence on this comparison in the review, the author was contacted to provide the data from the graphs.128
No studies were identified that assessed fibre intake or prebiotics. Further details of the included studies are detailed in Table 51. See also the study selection flow chart in Appendix E, study evidence tables in Appendix H, forest plots in Appendix K, GRADE tables in Appendix J and excluded studies list in Appendix M.
Table 52
Clinical evidence summary: probiotics versus placebo or usual care.
Table 53
Clinical evidence summary: omega-3 fatty acids versus placebo or usual care.
Table 54
Sanyal 2014 results table for outcomes reporting median (25th percentile, 75th percentile).
Table 55
Janczyk 2015 results table for outcomes reporting median (IQR) Omega-3 versus placebo in children and young people.
11.4. Economic evidence
11.4.1. Published literature
No relevant economic evaluations were identified.
See also the economic article selection flow chart in Appendix F.
11.4.2. Unit costs
See Table 90 in Appendix O.
11.5. Evidence statements
11.5.1. Clinical
Probiotics versus usual care or placebo
- In terms of NAFLD progression, moderate quality evidence suggested that probiotics had a beneficial effect in the reduction of the percentage of liver fat measured by MRS in adults over a period of equal to or greater than 3 to less than 12 months (n=20), and high quality evidence showed lower transient elastography fibrosis scores in those who were treated with probiotics compared with placebo controls (n=52).
- High to moderate quality evidence suggested that probiotic treatment for equal to or greater than 3 to less than 12 months has a beneficial effect on ALT levels in both adults (n=100) and children and young people (n=84). Low quality evidence also suggested a clinical benefit for probiotic treatment on AST levels in adults when compared to placebo or usual care (n=100).
- Moderate quality evidence suggested a small benefit of probiotics over placebo on weight loss in children and young people at equal to or greater than 3 to less than 12 months (n=64), although no benefit on weight loss was seen in adults (n=28).
- Moderate quality evidence suggested no difference in adverse events between the probiotic treatment groups or placebo groups in adults (n=52).
Omega-3 fatty acids versus usual care or placebo
- In terms of NAFLD progression, although the majority of evidence indicated some advantage of omega-3 fatty acids over placebo in adults, the imprecision of these effects was too large to allow conclusions to be drawn about clinical benefit or harm. The quality of evidence ranged from low to very low. Some advantage of omega-3 fatty acids was seen from low quality evidence in adults after treatment for greater than 12 months compared to placebo (n=174). Moderate quality evidence suggested a clinically important reduction in percentage of hepatic fat fraction content on MRI with omega 3 fatty acids in children compared to placebo after equal to or greater than 3 to less than 12 months of treatment (n=51).
- There was some low quality evidence for omega-3 fatty acids lowering the levels of ALT in adults after equal to or greater than 3 to less than 12 months of treatment compared to usual care (n=36) and high quality evidence for the same trend after greater than 12 month's treatment (n=137). Moderate quality evidence suggested a clinically important difference in final ALT levels in children and young people who had omega 3 fatty acids compared to placebo after equal to or greater than 3 to less than 12 months of treatment (n=51).
- There were similar small improvements in AST and less adverse events with omega-3 fatty acids in adults when treated for longer than 12 months (n=1-3). The evidence also suggested greater BMI (n=34) and more serious adverse events (n=243), however the imprecision of the effects were again too large to allow clinical conclusions to be drawn. The evidence ranged from high to low quality. Moderate to low quality evidence suggested no difference in clinical benefit in terms of weight loss in children and young people (2 RCTs; n=115). There was some evidence of benefit for reduction in BMI when considered as a dichotomous outcome of reduction of >5% but not when considered as continuous final BMI values. However, there is high quality evidence that fewer adverse events reported in adults receiving omega-3 fatty acids treatment for greater than 12 months than placebo (n=243). Low quality evidence suggested no difference in the adverse event of mild abdominal discomfort between treatment and control groups of children and young people (n=64).
11.5.2. Economic
- No relevant economic evaluations were identified.
11.6. Recommendations and link to evidence
| Recommendations |
|
|---|---|
| Research recommendation |
|
| Relative values of different outcomes | The GDG agreed that the outcomes that were critical to decision-making were progression of NAFLD, quality of life and occurrence of serious adverse events. Of these, progression of NAFLD as measured by liver biopsy was considered of greatest value for decision-making (with several studies using a composite of NAS less than or equal to 3 and fibrosis unchanged, or NAS decrease greater than or equal to 2 and fibrosis unchanged as the primary outcomes). The GDG agreed that other outcomes described within the identified evidence were also of clinical relevance; specifically, improvements in MRS intrahepatic triglyceride and improvements in transient elastography scores. Reduction in liver enzyme values and loss of weight were both agreed to be appropriate potential surrogate markers for improvement in NAFLD (and therefore considered as important outcomes), as were non-serious adverse events. |
| Trade-off between clinical benefits and harms | Probiotics: Five RCTs were identified investigating the clinical effectiveness of probiotic use in people with NAFLD (2 of which included children and young people). All of these studies defined the probiotic formulation administered and it was agreed that these were clinically appropriate formulations in each case. The meta-analyses of the 3 adult studies demonstrated improvements in several outcomes without the occurrence of notable adverse events; however, the GDG also noted that the magnitude of improvement in outcome measures tended to be so modest that their clinical significance was unclear. The GDG considered that the studies reviewed, that included children and young people with NAFLD, overall suggested a clinically relevant reduction in liver enzyme values in the treatment arm, but no significant improvements in any other of the reported outcomes. The GDG also noted that a higher rate of non-specific gastrointestinal side effects would have been expected with probiotics but this was not evident from this review. Overall, the GDG's interpretation of the reviewed evidence was that probiotics may have benefit for minimising progression of NAFLD in adults but that there is currently no evidence (from the limited data available) that probiotics may slow NAFLD progression in children and young people. The GDG observed that there was no evidence of probiotic use causing notable adverse events in people with NAFLD of any age. However, the GDG agreed that further research in this area is warranted, on a number of grounds. Firstly, there is a clear scientific rationale for why probiotics and manipulation of the gut microbiota may be effective in the treatment of NAFLD in children, young people and adults. Secondly, the identified studies were small and of variable quality yet still provided some promising data suggesting that NAFLD progression may be slowed through the use of probiotics, which merited consideration of larger and more robust studies within this area. Omega-3 fatty acids: All studies had defined the form of omega-3 fatty acid administered apart from 1; the GDG viewed the results of that study with caution, as the exact nature of the intervention was unclear. It was also noted that some people in the control arm in this study had been identified as using omega-3 fatty acids and that there was variable adherence within the intervention arm; this may have minimised observation of the full potential benefits of the omega-3 fatty acid intervention. It was noted that investigators in some studies had sought to define adherence by study participants to the intervention (for example, by measurement of erythrocyte percentage DHA and EPA enrichment by gas chromatography). The GDG agreed that the 4 studies considered assessing the effect of omega-3 fatty acids on NAFLD progression in adults with NAFLD14,159,165,166,179 did not overall demonstrate any significant improvements in clinically relevant outcomes. A slight decrease in adverse events and an even smaller increase in serious or severe adverse events was reported in adults with NAFLD randomised to receiving omega-3 supplements compared to the control group, but these differences were not large enough to be clinically important. The GDG also observed that regression analysis in the Scorletti 2014 study demonstrated that DHA (but not EPA) was independently associated with a decrease in liver fat percentage (as measured by MRS), but that the primary endpoint of progression of NAFLD as measured by liver biopsy was no different whether people with NAFLD were given omega-3 fatty acid supplements either containing DHA or without. The GDG also considered 3 studies assessing NAFLD progression in children with the condition treated with omega-3 fatty acids. There was some evidence of clinically relevant reductions in hepatic fat fraction (as assessed by MRI) and ALT in children and young people with NAFLD who were treated with DHA for 6 months. Collectively, the GDG concluded that there was insufficient evidence from the reviewed evidence for omega-3 fatty acids to be recommended at present to adults with NAFLD as a treatment to slow NAFLD progression. Whilst there was some supportive evidence for omega-3 fatty acids (specifically, DHA) slowing progression of NAFLD in children and young people with the condition, the GDG felt that as this was from a single study – with a relatively small cohort size – it was insufficient to allow the GDG to fully recommend DHA as therapy for children and young people with NAFLD. Therefore, the GDG agreed on a conclusion that DHA appears to have some effectiveness in this role. Other dietary interventions: No studies were identified relevant for inclusion regarding the other dietary interventions of fibre or prebiotics. As such, the GDG were unable to make any specific recommendations regarding such interventions. |
| Trade-off between net clinical effects and costs | No economic evidence was identified relating to any of the dietary supplements considered in this review. The GDG noted that the probiotic VSL#3 (containing sachets of lysophilised lactic acid bacteria) is listed within the BNF, but only ‘for use under the supervision of a physician for the maintenance of remission of ileoanal pouchitis only in adults as induced by antibiotics’ and so could not be prescribed by clinicians for people with NAFLD. No other probiotics are listed in the BNF. The GDG is not recommending that omega-3 fatty acid preparations should either be prescribed by clinicians or bought over-the-counter by people with NAFLD and so there are currently no economic considerations relating to these products. |
| Quality of evidence | Probiotics: The GDG noted that the number of identified studies was small and included only small numbers of participants with variable lengths of follow-up. The information given within the identified studies regarding the means taken to assess compliance with the intervention was often limited. For these reasons, and the imprecision associated with the effects, the majority of evidence was rated as low to moderate quality. A high quality GRADE rating was observed for 2 outcomes; NAFLD progression assessed by transient elastography fibrosis score and ALT levels in adults at greater than or equal to 3 to 12 months. Omega-3 fatty acids: The majority of the evidence was rated as low risk of bias as the identified RCTs were overall well-designed, adequately powered studies with appropriate outcomes that together gave sufficient data to allow meaningful conclusions to be reached regarding the clinical efficacy of this intervention. However, the imprecision associated with the effects for many outcomes lead to the majority of evidence being rated as moderate quality. A high-quality GRADE rating was observed for 3 outcomes; ALT levels, AST levels and adverse events for adults at greater than or equal to 12 months. |
| Other considerations | Research recommendation The GDG made a high-priority research recommendation to investigate the clinical and cost-effectiveness of probiotics and prebiotics to treat NAFLD. See Appendix Q for further details. |
- Dietary modification and supplements - Non-Alcoholic Fatty Liver DiseaseDietary modification and supplements - Non-Alcoholic Fatty Liver Disease
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