Clinical review protocols

National Guideline Centre (UK)

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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.)

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Non-Alcoholic Fatty Liver Disease: Assessment and Management.

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Appendix CClinical review protocols

C.1. Risk factors for NAFLD

Table 1Review protocol: Risk factors for NAFLD

Review question	Which risk factors for NAFLD or severe NAFLD (NASH, fibrosis) aid in the identification of people who should be investigated further?
Objectives	To determine the risk of NAFLD or severe NAFLD for people with different risk factors (to provide guidance on who should be investigated for diagnosis rather than relying on opportunistic case finding).
Population	Adults (18 years and over) Young people (11 years or older and younger than 18 years) and children (younger than 11 years)
Prognostic variable	Waist circumference BMI Raised triglycerides Low HDL-cholesterol Type 2 diabetes (HOMA-IR, HbA1c) Hypertension (Blood pressure; systolic or diastolic) Age Combinations of the above
Outcomes	Diagnosis of NAFLD Diagnosis of NASH/fibrosis
Review strategy	Prospective and retrospective cohorts with multivariate analysis that adjust for ≥3 of the above confounders in their model.
Exclusions	Studies that state fewer than 3 of the above risk factors in the adult population (unless no other multivariate studies available for the young people population) Studies with fewer than 10 participants per confounder for both the adult and young people population Stepwise multivariate analysis (unless no other multivariate analysis studies available). Univariate-based analysis Conference abstracts.
How the information will be searched	The databases to be searched are Medline, Embase, the Cochrane Library. Studies will be restricted to English language only
Key confounders	Factors independently associated with prognostic variable: Waist circumference BMI Raised triglycerides Low HDL-cholesterol Type 2 diabetes Hypertension Age Vitamin D levels

C.2. Diagnosis of NAFLD

Table 2Review protocol: Diagnosis of NAFLD

Review question	What is (are) the appropriate investigation(s) for diagnosing NAFLD in adults, young people and children?
Objectives	To evaluate the accuracy of the diagnostic tests for NAFLD. To compare the accuracy of the diagnostic tests.
Study design	Prospective and retrospective diagnostic accuracy cohort studies
Population	Combined population of adults (18 years and over), children and young people (aged >5 years to <18 years)
Index test(s)	Alanine transaminase (ALT) Aspartate aminotransferase (AST) Controlled Attenuation Parameter (CAP) test (M probe, XL probe) Fatty liver index (FLI) (0–100 scale:<30 not fatty liver, >60 is fatty liver) Gamma GT MRI or MRS (MRS-looking at fat in a small area in the liver) NAFLD liver fat score SteatoTest Liver ultrasound Combination of tests
Reference standard	Liver biopsy (for example, NAFLD activity score [NAS] [synonymous with NASH-CRN])
Statistical measures	Diagnostic accuracy: Sensitivity Specificity Positive predictive value Negative predictive value Positive likelihood ratio Negative likelihood ratio ROC curve or area under curve (AUC)
Exclusions	Post-liver transplant studies
Search strategy	The databases to be searched are Medline, Embase, the Cochrane Library. Studies will be restricted to English language only Conference abstracts will be excluded
Review strategy	Any combination(s) of tests identified. Diagnostic meta-analysis will be undertaken if appropriate (when there are 3 or more studies where 2×2 data are available for the same threshold (or agreed similar). Pooling within specific threshold ranges in consultation with GDG. In recognition that NAFLD is a partly clinical diagnosis (assessment of alcohol intake) the target conditions reported by papers which will be taken into consideration for fatty liver are: steatosis 5% and 30-34% (as reported by studies). Appraisal of methodological quality: The methodological quality of each study will be assessed using the QUADAS-2 checklist.

C.3. Diagnosing the severity of NAFLD

Table 3Review protocol: Diagnosing the severity of NAFLD

Review question	Which assessment tools are most accurate in identifying the severity or stage of NAFLD in adults, young people and children with NAFLD?
Objective	To determine the diagnostic accuracy of tests used to diagnose the severity and different stages of NAFLD from simple steatosis to NASH, through to fibrosis and up to the point of cirrhosis (and therefore to determine which tools should be used and on whom they should be used)
Population	Combined population of adults (18 years and over), children and young people (aged >5 years to <18 years) with NAFLD (any form of diagnosis).
Index tests (assessment tools)	For NASH Cytokeratin-18 AST/ALT ratio ALT Ferritin NASH test For fibrosis (any ≥F1 or advanced ≥F3) Acoustic radiation force impulse imaging (ARFI) ALT levels AST/ALT ratio AST-to-platelet ratio index (APRI) BARD score Diffusion weighted magnetic imaging ELF test Ferritin Fib-4 Fibrometer FibroTest MRI MRS MR elastography NAFLD fibrosis score Shear wave elastography Transient elastography
Reference standard	Liver biopsy (graded and staged according to Brunt or Kleiner: NAFLD activity score [NAS] [synonymous with NASH-CRN])
Outcomes	Diagnostic accuracy: Specificity Sensitivity Positive predictive value Negative predictive value Positive likelihood ratio Negative likelihood ratio ROC curve or area under curve (AUC)
Exclusion	Post-liver transplant studies Secondary fatty liver Conference abstracts
Search strategy	The databases to be searched are Medline, Embase, the Cochrane Library. Studies will be restricted to English language only
The review strategy	Prospective diagnostic cohorts; if none identified, retrospective diagnostic cohorts. Any combination(s) of tests identified. Diagnostic meta-analysis will be undertaken if appropriate (when there are 3 or more studies where 2×2 data are available for the same threshold (or agreed similar). Pooling within specific threshold ranges in consultation with GDG. In recognition that NAFLD is a partly clinical diagnosis (assessment of alcohol intake) the target conditions reported by papers which will be taken into consideration for fatty liver are: steatosis 5% and 30-34% (as reported by studies). Appraisal of methodological quality: The methodological quality of each study will be assessed using the QUADAS-2 checklist. Severity of disease: simple steatosis to non-alcoholic steatohepatitis (NASH) fibrosis focusing on any fibrosis (F≥1) and advanced fibrosis (≥F3) cross refer to cirrhosis guideline for specific occurrence of fibrosis F4.

C.4. Monitoring NAFLD progression

Table 4Review protocol: Monitoring NAFLD progression

Review question	How often should we monitor adults, young people and children with NAFLD or NASH (with or without fibrosis) to determine risk of disease progression?
Objectives	To identify the rate of progression in people with NAFLD and hence who (for example, people with severe NAFLD) should be monitored for disease progression and how often.
Population	Adults with NAFLD (18 years and over) Young people with NAFLD (11 years or older and younger than 18 years), children with NAFLD (younger than 11 years)
Presence / absence of prognostic variable	Presence of NAFLD
Outcomes	Rate of: Progression from NAFLD to NASH Progression from NASH to NASH with fibrosis Progression from NASH with fibrosis to cirrhosis
Exclusions	Univariate-based analysis Conference abstracts Multivariate analysis that adjust for <3 of the above confounders Cross-sectional design
How the information will be searched	The databases to be searched are Medline, Embase, and The Cochrane Library. Studies will be restricted to English language only
Key confounders	To be identified; factors independently associated with prognostic variable: Waist circumference BMI Raised triglycerides Low HDL-cholesterol Type 2 diabetes Hypertension Age
The review strategy	RCTs, systematic reviews and Prospective and retrospective cohorts, (where multivariate analysis that state ≥3 of the above risk factors). Where studies have adjusted for more than the 3 critical confounders the results will be presented with a description.

C.5. Extra-hepatic conditions

Table 5Review protocol: Extra-hepatic conditions

Review question	Should a diagnosis of NAFLD in adults, young people and children prompt assessment for additional extra-hepatic conditions and, if so, which?
Objectives	To determine the level of increased risk of extra-hepatic conditions associated with NAFLD.
Population	Adults (18 years and over), young people (11 years or older to younger than 18 years) and children (younger than 11 years and older than 5 years) with NAFLD.
Prognostic variable	Presence of NAFLD
Outcomes	Critical: Cardiovascular disease (MI, stroke, TIA, angina, PAD, hypertension) Type 2 diabetes Colorectal cancer Dyslipidaemia (hypertriglyceridemia) Important: Polycystic ovarian syndrome (PCOS) for adults and young people Chronic kidney disease (CKD) Obstructive sleep apnoea syndrome Vitamin D levels Obesity (BMI) Insulin resistance
Review strategy	Prospective and retrospective cohorts, and case–control studies with multivariate analysis that adjust for ≥3 of the above confounders in their model. While the presence of NAFLD was the primary prognostic variable identified by the GDG, papers will also be included which investigate the relationship between severity/stage of NAFLD and the identified extra-hepatic conditions.
Other exclusions	Conference abstracts, cross-sectional studies, univariate analysis, multivariate analysis that adjust for <3 listed confounders.
Search strategy	The databases to be searched are Medline, Embase, the Cochrane Library. Studies will be restricted to English language only
Key confounders	Critical confounders: BMI Gender Age Diabetes (needs to be adjusted for only because it's a risk factor for CVD) Important confounders: Metabolic syndrome Blood pressure

C.6. Weight reduction interventions

Table 6Review protocol: Weight reduction interventions

Review question	What is the clinical and cost-effectiveness of dietary interventions for weight reduction for adults, young people and children with NAFLD compared with standard care?
Guideline condition and its definition	Non-alcoholic fatty liver disease (NAFLD)
Objectives	To estimate the effectiveness and cost-effectiveness of dietary interventions that are intended to result in weight reduction in the management of people with NAFLD.
Review population	People with NAFLD
	Adults > 18 years Young people; 11 to 18 years and children; younger than 11 years
	Line of therapy not an inclusion criterion
Interventions and comparators: generic/class; specific/drug (All interventions will be compared with each other, unless otherwise stated)	Weight reduction; Low fat Weight reduction; Low carbohydrate Weight reduction; High protein Weight reduction; High fibre Weight reduction; Higher percentage fat Weight reduction; Lower percentage fat Weight reduction; Higher percentage carbohydrate Weight reduction; Lower percentage carbohydrate Weight reduction; Higher percentage protein Weight reduction; Lower percentage protein Weight reduction; Very low calorie diet (VLCD)/extreme restriction/meal replacement Placebo / active control; Placebo Placebo / active control; Active control No intervention / standard care; No intervention No intervention / standard care; Standard care
Outcomes	- Quality of life at >3 months to <6 months (Continuous) CRITICAL - Length of stay at >3 months (Continuous) IMPORTANT - Hospitalisation at >3 months (Dichotomous) IMPORTANT - NAFLD progression with liver biopsy at 12 months and greater (Continuous) CRITICAL - NAFLD progression with MRI / MRS at 12 months and greater (Continuous) CRITICAL - NAFLD progression with ultrasound at 12 months and greater (Continuous) CRITICAL - NAFLD progression with Enhanced Liver Fibrosis (ELF) score at 6 months to >12 months (Continuous) CRITICAL - Liver function tests (for example ALT levels, ALT/AST ratio) at >3 months to <6 months (Continuous) CRITICAL - NAFLD progression with fibroscan/ transient elastography at >3 months to <6months (Continuous) CRITICAL - NAFLD progression with NAFLD fibrosis score at >3 months to <6 months (Continuous) CRITICAL - Weight loss at >3 months and < 6 months (Continuous) IMPORTANT - NAFLD progression with fibroscan/ transient elastography at 6 months to <12 months (Continuous) CRITICAL - NAFLD progression with fibroscan/ transient elastography at 12 months and greater (Continuous) CRITICAL - NAFLD progression with NAFLD fibrosis score at 12 months and greater (Continuous) CRITICAL - NAFLD progression with NAFLD fibrosis score at 6 months to <12 months (Continuous) CRITICAL - Liver function tests (for example ALT levels, ALT/AST ratio) at 12 months and greater (Continuous) CRITICAL - Liver function tests (for example ALT levels, ALT/AST ratio) at 6 months to <12 months (Continuous) CRITICAL - NAFLD progression with liver biopsy at 6 months to <12 months (Continuous) CRITICAL - NAFLD progression with liver biopsy at >3 months to <6 months (Continuous) CRITICAL - NAFLD progression with ultrasound at 6 months to < 13 months (Continuous) CRITICAL - NAFLD progression with ultrasound at >3 months to < 6 months (Continuous) CRITICAL - NAFLD progression with Enhanced Liver Fibrosis (ELF) score at 12 months and greater (Continuous) CRITICAL - NAFLD progression with Enhanced Liver Fibrosis (ELF) score at >3 months to <6 months (Continuous) CRITICAL - Liver function tests (for example ALT levels, ALT/AST ratio) at 12 months and greater (Continuous) CRITICAL - Liver function tests (for example ALT levels, ALT/AST levels) at 6 months to < 12 months (Continuous) CRITICAL - Quality of life at 6 months to <12 months (Continuous) CRITICAL - Quality of life at 12 months and greater (Continuous) CRITICAL - Weight loss at 12 months and greater (Continuous) IMPORTANT - Weight loss at 6 months to <12 months (Continuous) IMPORTANT - NAFLD progression with MRI / MRS at >3 months to < 6 months (Continuous) CRITICAL - NAFLD progression with MRI / MRS at 6 months to <12 months (Continuous) CRITICAL - NAFLD progression with liver biopsy Composite of NAS ≤3/fibrosis unchanged or decrease NAS ≥2 fibrosis unchanged at 3 months and greater (Dichotomous) CRITICAL - NAFLD progression with liver biopsy NAS ≤3/fibrosis unchanged at 3 months and greater (Dichotomous) CRITICAL - NAFLD progression with liver biopsy decrease NAS ≥2 fibrosis unchanged at 3 months and greater (Dichotomous) CRITICAL - Any adverse event at Greater or equal to 3 months (Dichotomous) IMPORTANT - Serious adverse event at Greater or equal to 3 months (Dichotomous) IMPORTANT - Severe adverse event at Greater or equal to 3 months (Dichotomous) IMPORTANT - Any adverse event at 3 months or greater (Dichotomous) IMPORTANT - Severe adverse events at 3 months or greater (Dichotomous) IMPORTANT - Serious adverse event at 3 months or greater (Dichotomous) IMPORTANT - Weight (kg) at 3 months and greater (Continuous) IMPORTANT
Study design	Systematic Review RCT Comparative prospective cohort study
Unit of randomisation	Patient
Crossover study	Not permitted
Minimum duration of study	12 weeks
Population stratification	Adults (18 years and over) Young people (11 years or older and younger than 18 years) Children (younger than 11 years) Young people (11 years or older and younger than 18 years) and children (younger than 11 years combined)
Reasons for stratification	Combined young people and children
Subgroup analyses if there is heterogeneity	None specified
Search criteria	Databases: Date limits for search: Language:

C.7. Dietary modification and supplements

Table 7Review protocol: Dietary modification and supplements in the management of NAFLD

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?
Objective	To estimate the effectiveness and cost-effectiveness of dietary modifications and supplements in the management of people with NAFLD.
Population	Adults with NAFLD (18 years and over) Young people with NAFLD (11 years or older and younger than 18 years), and children with NAFLD (younger than 11 years) [NB adults and children pooled for Omega-3 fatty acids, but separate for probiotics and fibre/prebiotics]
Intervention	Supplements: Omega-3 fatty acids Probiotics Fibre/prebiotic
Comparison	No intervention, standard care (for example, advice) or control
Outcomes	Critical outcomes: Progression of NAFLD as assessed by: Liver biopsy MRI/MRS (combine as measure fat in liver) Ultrasound (absence of steatosis only) The Enhanced Liver Fibrosis (ELF) score Transient elastography NAFLD fibrosis score Quality of life (for example CLDQ, EQ-5D) Serious adverse events Important outcomes: Weight loss Liver function tests (ALT and AST levels) Adverse events
Exclusion	Dietary advice/behaviour modification /counselling
	The databases to be searched are Medline, Embase, The Cochrane Library, nursing data bases, Amed (allied medicine and dietary interventions) Studies will be restricted to English language only
The review strategy	RCTs, Systematic Reviews of RCTs If no RCTs or SRs identified, prospective cohort studies Search terms: micronutrients
Analysis	A meta-analysis will be conducted on RCTs with appropriate outcome data. Outcomes to be assessed at the following study follow-up times; ≥3 months to <12 months ≥12 months

C.8. Exercise interventions

Table 8Review protocol: Exercise interventions in the management of NAFLD

Review question	What is the clinical and cost-effectiveness of exercise programmes for adults, young people and children with NAFLD compared with standard care?
Guideline condition and its definition	Non-alcoholic fatty liver disease (NAFLD)
Objectives	To estimate the clinical effectiveness and cost-effectiveness of exercise interventions in the management of people with NAFLD
Review population	People with NAFLD
	Adults > 18 years Young people; 11 to 18 years Children; younger than 11 years All ages
Line of therapy	Line of therapy not an inclusion criterion
Interventions and comparators: generic/class; specific/drug (All interventions will be compared with each other, unless otherwise stated)	Exercise; Aerobic exercise / cardio-exercise Exercise; Resistance exercise / repeated muscle contraction (strength, anaerobic endurance) Exercise; High intensity training (alternate intense anaerobic and recover) Activities of daily living; physical activity (general everyday) Activities of daily living; Reducing sedentary time Control; usual care Control; sham Control; no treatment
Outcomes	Critical outcomes: Progression of NAFLD as assessed by: Liver biopsy (for example, NAFLD activity score [NAS] [synonymous with NASH-CRN]) MRI or MRS Ultrasound (absence of steatosis only) The Enhanced Liver Fibrosis (ELF) score Transient elastography NAFLD fibrosis score Quality of life (for example CLDQ, EQ-5D) Serious adverse events Important outcomes: Liver function tests (for example, ALT and AST levels, ALT/AST ratio) Weight Adverse events Outcomes to be assessed at the following study follow-up times: ≥3 months to <12 months ≥12 months
Exclusion	Conference abstracts
Study design	Systematic Review RCT
Unit of randomisation	Patient
Crossover study	Not permitted
Minimum duration of study	12 weeks
Population stratification	Adults (18 years and over) Young people (11 years or older and younger than 18 years Children (younger than 11 years)
Reasons for stratification	Recommendations may differ for each population strata.
Sensitivity/other analysis	Ethnicity
Subgroup analyses if there is heterogeneity	None specified
Search criteria	Databases: Date limits for search: Language:

C.9. Lifestyle modification

Table 9Review protocol: Lifestyle modification in the management of NAFLD

Review question	What is the clinical and cost-effectiveness of lifestyle modification programmes for diet and exercise interventions for adults, young people and children with NAFLD compared with diet alone, exercise alone or standard care?
Guideline condition and its definition	NAFLD
Objectives	To estimate the clinical effectiveness and cost-effectiveness of lifestyle modification interventions in the management of people with NAFLD
Review population	Adults with NAFLD (18 years and over) Young people with NAFLD (11 years or older and younger than 18 years), and children with NAFLD (younger than 11 years)
Interventions and comparators	Interventions: Lifestyle modification; Any diet plus any exercise plus any behavioural therapy Diet and exercise; Any diet with any exercise Comparators: Control: no intervention, control, usual care Diet: any diet Exercise: any exercise
Outcomes	Critical outcomes: Progression of NAFLD as assessed by: Liver biopsy MRI/MRS Ultrasound (absence of steatosis only) The Enhanced Liver Fibrosis (ELF) score Transient elastography NAFLD fibrosis score Quality of life (for example, CLDQ, EQ-5D) Serious adverse events Important outcomes: Weight Liver function tests (for example, ALT, AST levels, ALT/AST ratio) Adverse events
Study design	RCT Systematic Review Prospective cohort study
Unit of randomisation	Patient
Crossover study	Not permitted
Minimum duration of study	12 weeks
Subgroup analyses if there is heterogeneity	Type of exercise Type of exercise Type of diet Follow-up
Search criteria	Databases: Date limits for search: no date limit Language: English only

C.10. Alcohol advice

Table 10Review protocol: Alcohol advice for people with NAFLD

Review question	Should people with NAFLD restrict their consumption of alcohol to below national recommended levels?
Objective	To investigate the relationship between alcohol consumption and NAFLD, to identify if adults with a diagnosis of NAFLD should be advised to abstain from drinking alcohol completely or if there are safe limits.
Population	Adults with NAFLD (18 years and over)
Prognostic variables	Alcohol consumption (continuous outcome) Or No alcohol compared with alcohol within national limits (categorical)
Key confounding factors	Age Diabetes BMI
Outcomes	Critical outcomes: Progression of NAFLD as assessed by: Liver biopsy (for example, NAFLD activity score [NAS] [synonymous with NASH-CRN]) MRI or MRS Ultrasound (absence of steatosis only) The Enhanced Liver Fibrosis (ELF) score Transient elastography NAFLD fibrosis score
Exclusion	Univariate analysis Conference abstracts Cross-sectional studies MVA that control for <3 confounders
Search strategy	The databases to be searched are Medline, Embase, the Cochrane Library. Studies will be restricted to English language only
The review strategy	RCTs, systematic reviews and prospective and retrospective cohorts with multivariate analysis that adjust for ≥3 of the above confounders in their model.

C.11. Fructose advice

Table 11Review protocol: Fructose advice

Review question	Should people with NAFLD restrict their consumption of fructose or sugar (sucrose)?
Objectives	To investigate the relationship between fructose consumption and NAFLD, to identify if people with a diagnosis of NAFLD should be advised to restrict their consumption of fructose or sugar (sucrose).
Population	Adults with NAFLD (18 years and over) Young people with NAFLD (11 years or older and younger than 18 years) and children with NAFLD (younger than 11 years)
Presence / absence of prognostic variable	Pool these 2 types of carbohydrate, then subgroup if there is heterogeneity: Fructose Sugar (sucrose)
Outcomes	Critical outcomes: Progression of NAFLD as assessed by: Liver biopsy (for example, NAFLD activity score [NAS] [synonymous with NASH- CRN]) MRI or MRS Ultrasound (absence of steatosis only) The Enhanced Liver Fibrosis (ELF) score Transient elastography NAFLD fibrosis score Important outcomes: Liver function tests (for example ALT levels, ALT/AST ratio) Adverse events
Study design	RCTs systematic reviews cohort studies, or if none of the previous then case-control studies would be considered.
Exclusions	Univariate-based analysis Conference abstracts Cross-sectional studies Multivariate analyses that control for <3 confounders
How the information will be searched	The databases to be searched are Medline, Embase, the Cochrane Library. Studies will be restricted to English language only
Key confounders	Age BMI Diabetes

C.12. Caffeine advice

Table 12Review protocol: Caffeine advice

Review question	Should people with NAFLD modify their consumption of caffeine from coffee?
Objectives	To determine if caffeine from coffee is a protective factor on the progression of NAFLD
Review population	Adults (18 years and over), young people (11 years or older to younger than 18 years) and children (younger than 11 years and older than 5 years) with NAFLD.
Prognostic variable	Coffee; Caffeine
Outcomes	Critical outcomes: Progression of NAFLD as assessed by: Liver biopsy MRI/MRS Ultrasound (absence of steatosis only) The Enhanced Liver Fibrosis (ELF) score Transient elastography NAFLD fibrosis score Serious adverse events Quality of life Important outcomes: Weight (BMI, wait circumference) Liver function tests (for example, ALT, AST levels, ALT/AST ratio)
Study design	Systematic Review RCT Prospective or retrospective cohort studies If none of the above identified then case-control studies with multivariable analysis would be considered.
Search strategy	The databases to be searched are Medline, Embase, the Cochrane Library. Studies will be restricted to English language only

C.13. Pharmacological interventions

Table 13Review protocol: Pharmacological interventions

Review question	What is the clinical and cost-effectiveness of pharmacological interventions for adults, young people and children with NAFLD?
Guideline condition and its definition	NAFLD. Definition: Non-alcoholic fatty liver disease
Objectives	To estimate the clinical and cost-effectiveness of pharmacological interventions in the management of patients with NAFLD
Review population	People with NAFLD
	Greater or equal to 18 years of age <18 years of age
	Line of therapy not an inclusion criterion
Interventions and comparators: generic/class; specific/drug (All interventions will be compared with each other, unless otherwise stated)	Insulin sensitisers: pioglitazone Insulin sensitisers: metformin Ursodeoxycholic acid Vitamin E Pentoxifylline Statins ACE inhibitors Angiotensin II receptor blockers (ARBs) Alpha blockers Orlistat GLP-1 receptor agonists Dipeptidyl peptidase-4 DPP4 enzyme inhibitors Combination of 2 pharmacological interventions Placebo
Outcomes	- Quality of life at ≥3 to <12 months (Continuous) CRITICAL - Quality of life at ≥12 months (Continuous) CRITICAL - Mortality at ≥12 months (Time to event) CRITICAL - Mortality at ≥3 to <12 months (Time to event) CRITICAL - Progression of NAFLD at ≥3 to <12 months (Continuous) CRITICAL - Progression of NAFLD at ≥12 months (Continuous) CRITICAL - Serious adverse events at ≥3 to <12 months (Dichotomous) CRITICAL - Serious adverse events at ≥12 months (Dichotomous) CRITICAL - Adverse events at ≥12 months (Dichotomous) IMPORTANT - Adverse events at ≥3 to <12 months (Dichotomous) IMPORTANT - Liver function tests at ≥3 to <12 months (Continuous) IMPORTANT - Liver function tests at ≥12 months (Continuous) IMPORTANT
Study design	Systematic review RCT Non-randomised comparative study
Unit of randomisation	Patient
Crossover study	Not permitted
Minimum duration of study	3 months
Other exclusions	Other liver disease aetiology Conference abstracts
Population stratification	Adults Young people and children
Reasons for stratification	Differences in drug dosages and possible different responses to treatment
Sensitivity/other analysis	Pooling across doses
Subgroup analyses if there is heterogeneity	- Extra-hepatic condition (Type 2 diabetes; Insulin resistance; Hypertension; dyslipidaemia); Concomitant treatment
Search criteria	Databases: Medline, Embase, Cochrane library Date limits for search: N/A Language: Restricted to English language only

Bookshelf ID: NBK384745

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