TABLE 3.
Characteristics of intervention studies that examined effects of monosaccharide fructose, sucrose, HFCS, other fructose-supplemented, or fructose-reduced diets on indexes of liver health1
| First author, pub year (ref) [country]; study design | Participants (ethnicity) | Participants enrolled/analyzed | M | Baseline age, (range)2 | BMI or body weight3 | Source of dietary fructose in interventions | Interventions (participants) | Energy balance of study design | Duration of intervention (washout duration) | Outcomes assessed (primary or secondary endpoint) | Funding source | Risk of bias |
| n | % | y | ||||||||||
| Adults | ||||||||||||
| Aeberli, 2011 (46) [Switzerland]; crossover RCT | Healthy M living in Zurich (NR) | 29/24 | 100.0 | 26.3 (NR) | 22.4 kg/m2 | Fructose, sucrose, or glucose sweetened SSBs | Fructose in SSB, 40, 80 g/d compared with sucrose in SSB, 40, 80 g/d, compared with glucose in SSB, 40, 80 g/d (n = 25–27) | Hypercaloric | 3 wk (4 wk) | AST, ALT (secondary) | Nonprofit and industry | Low |
| Al-Waili, 2003 (52) [United Arab Emirates]; before-and-after trial | Healthy volunteers from medical staff (NR) | 10/10 | 70.0 | 31.2 (20–45) | NR | Honey, 1.2 g/kg body weight | Fructose, 0.46 g fructose/kg body weight (n = 10) | Hypercaloric | 2 wk | ALT, AST, ALP (NR) | NR | Medium |
| Bravo, 2013 (59) [United States]; parallel RCT | Healthy men and women, not taking any prescription medicine or over-the counter products for weight loss (NR) | 80/64 | 56 | 38.7 (20–60) | 23–35 kg/m2 | HFCS-55 or sucrose-sweetened low-fat (1%) milk | HFCS at 8% (n = 8), 18% (n = 12), or 30% (n = 11) of energy requirement compared with sucrose at 8% (n = 13), 18% (n = 10), or 30% (n = 10) of energy requirement | Isocaloric (on the basis of lack of significant differences in total energy intake or body weight during study) | 10 wk | Liver fat by unenhanced computed tomography (primary) | Industry | Medium |
| Couchepin, 2008 (53) [Switzerland]; crossover RCT | Healthy young M and F adults (white) | 16/16 | 50.0 | 22.7 (NR) | 21.8 kg/m2 | NR | Fructose, 3.5 g/kg fat-free mass/d (+38% of daily energy) compared with isocaloric diet (n = 16) | Hypercaloric | 6 d (28 d) | ALT (NR) | Nonprofit | Medium |
| Faeh, 2005 (55) [Switzerland]; before-and-after trial | Healthy, young adult M (NR) | 7/7 | 100.0 | NR (22–31) | 71.5 kg | D-Fructose (Fluka Chemie Gmbh) in as a 20% fructose solution with 3 main meals | Fructose, 3 g/kg body weight (n = 7)4 | Hypercaloric | Fructose, 6 d (isocaloric diet given 3 d before intervention and acted as washout between interventions) | Hepatic de novo lipogenesis (NR) | Nonprofit | High |
| Johnston, 2013 (67) [United Kingdom]; parallel RCT | Healthy centrally overweight men, aged 18–50 y (NR) | 32/32 | 100.0 | 34 (NR) | 29 kg/m2 | Monosaccharaides were consumed 4 times/d in divided amounts mixed with 500 mL H2O | Fructose, 25% total energy requirements compared with glucose 25% total energy requirements | Isocaloric (period 1) and hypercaloric (period 2) | 2 wk | IHCLs (primary); ALT, AST, GGT (secondary) | Nonprofit | Low |
| Kelsay, 1974 (60) [United States]; crossover RCT | Healthy F students at the University of Maryland (NR) | 8/8 | 0.0 | NR (18–23) | 43.6–65.3kg | Uncooked fondant patties made with sucrose | Sucrose, 850 kcal/d compared with glucose, 850 kcal/d compared with isocaloric diet (n = 8) | Isocaloric | Sucrose and glucose, 4 wk (control consumed 1 wk before each period and 2 wk washout between sucrose and glucose) | ALKP, ALT, AST (NR) | NR | Medium |
| Koh, 1988 (47) [United States]; Non-RCT | IGT adults. Controls: University and faculty staff (NR) | 18/18 | IGT: 33; control: 33 | IGT: 54 (NR); control: 50 (NR) | IGT: 164 lb; control: 145 lb | Free fructose in packets, mixed with unsweetened fruit juice, milk, and water | Fructose, 15% total energy compared with glucose packets, 15% total energy (n = 18)5 | Isocaloric | 4 wk | Bilirubin (NR) | NR | Medium |
| Lê, 2006 (56) [Switzerland]; before-and-after trial | Healthy, moderately physically active, young adult M | 7/7 | 100 | 24.7 (NR) | 69.3 kg | Pure fructose in 20% solution with the 3 main meals | Fructose, 1.5 g · kg−1 · d−1 representing an excess of 18% of the daily energy requirement (n = 7) | Hypercaloric | 4 wk | IHCLs (NR) | Nonprofit | High |
| Lê, 2009 (54) [Switzerland]; crossover RTC | Healthy, M adult offspring of type 2 diabetes patients and healthy M adults | 24/24 | 100 | 24.7 (NR) | NR | Pure fructose in 20% solution | Fructose, 3.5 g · kg−1 · d−1 compared with isocaloric diet (n = 24) | Hypercaloric | 7 d (4–5-wk washout) | IHCLs (primary), ALT (secondary) | Nonprofit and industry | High |
| Maersk, 2012 (61) [Denmark]; parallel RCT | Healthy, nondiabetic, middle-aged adults | 60/47 | 37 | 38.7 (20-50) | 32 kg/m2 | Sucrose-sweetened cola (Coca Cola) | Sucrose 106 g/d (n = 10) compared with diet cola (n = 12) compared with semi-skimmed milk (n = 12) compared with water (n = 13) | Isocaloric (on the basis of dietary questionnaire and weight change) | 6 mo | IHCLs (primary) | Government, nonprofit, and industry | High |
| Ngo Sock, 2010 (48) [Switzerland]; crossover RCT | Healthy, moderately physically active adult M | 11/11 | 100 | 24.6 (NR) | NR | Pure fructose in 20% solution | Fructose, 3.5 g · kg−1 · d−1 compared with glucose, 3.5 g · kg−1 · d−1 compared with weight-maintenance diet (n = 11) | Hypercaloric | 7 d (2–3-wk washout) | IHCLs (primary); ALT, AST (secondary) | Nonprofit | Medium |
| Perez-Polo, 2010 (57) [Spain]; before-and-after trial | Healthy, older adult M (NR) | 74 | 100.0 | 51 (NR) | 28.5 kg/m2 | Free fructose in 10% solution | Fructose, 200 g/d (n = 36); fructose with allopurinol, 200 g/d (n = 38) | Hypercaloric | 2 wk | ALT, AST, GGT (secondary) | Nonprofit | Medium |
| Porikos, 1983 (62) [United States]; before-and-after trial | Middle-aged adult M (NR) | 21 | 100.0 | NR (24-45) | NR6 | Snacks and food with sucrose | Sucrose, 25–30% kcal (n = 21) | Hypercaloric | 30 d | ALT, AST (primary) | Government and industry | High |
| Purkins, 2004 (63) [UK]; crossover RCT | Healthy adult M (NR) | 12 /12 | 100.0 | NR (20-41) | NR | Readily available sucrose-containing food | High-carbohydrate diet (sucrose, 1408 kcal/d; 4500 kcal/d), compared with high-fat diet (sucrose 180 kcal/d; 4500 kcal/d) compared with standard diet (1900 kcal/d) (n = 12) | Hypercaloric | 8 d (14-d washout) | ALP, ALT, AST, GGT, bilirubin (primary) | Industry | High |
| Silbernagel, 2011 (50); Silbernagel, 2012 (49) [Germany]; parallel RCT | Healthy, middle-aged adults | 25/20 | 60 | 30.5 (20–50) | 25.9 kg/m2 | Pure fructose powder dissolved in water | Fructose, 150 g/d (n = 10) compared with glucose, 150 g/d (n = 10) | Hypercaloric | 4 wk | IHCLs (primary) | Nonprofit | High |
| Sobrecases, 2010 (58) [Switzerland]; non-RCT | Healthy adult M | 30/30 | 100 | 23.9 (NR) | 22.6 kg/m2 | NR | Fructose, 3.5 g/kg (n = 12) compared with high fat, 30% total energy as saturated fat (n = 10) compared with fructose plus high fat (n = 8) | Hypercaloric | Fructose: 7 d, high fat and fructose and high fat: 4 d | IHCLs (primary), ALT (secondary) | Nonprofit | High |
| Stanhope, 2009 (51); Cox, 2012 (68) [United States]; parallel RCT | Healthy, older adults (NR) | First 23 enrolled people/18 (DNL outcome); 39/32 (liver enzyme outcomes) | 50.0 | 53.7 (NR) | 29.3 kg/m2 | Free fructose added to unsweetened beverage (Kool-Aid; Kraft) | Fructose (+25% of daily energy) (n = 10) compared with glucose SSB (+25% of daily energy) (n = 8) | Hypercaloric | 10 wk7 | Hepatic de novo lipogenesis, ALT, AST, GGT (NR) | Government | High (DNL outcome); medium (liver enzyme outcomes) |
| Theytaz, 2012 (64) [Switzerland]; crossover RCT | Healthy, nonobese, nonsmokers, and sedentary M | 9/9 | 100 | 23.3 (NR) | 22.6 kg/m2 | Pure fructose provided as drinks 5 times/d | Fructose, 3 g/kg, + essential amino acid (+38% of daily energy) compared with Fructose, 3 g/kg plus placebo (+36% of daily energy) compared with weight-maintenance diet (n = 9) | Hypercaloric | 6 d (4–10-wk washout) | IHCLs (primary) | Industry | Medium |
| Volynets, 2012 (69) [Germany]; before-and-after trial | Patients with NAFLD, diagnosed by ultrasound and blood variables (NR) | 15/10 | 40 | 45.5 (34.5–51.5) | 31.1 | Reduction in the consumption of fructose-rich foods (eg, to avoid sweets, lemonades, fruit juices) and to prefer foods with a lower content of fructose | Nutritionists advised patients to reduce their daily fructose intake by 50% | Hypocaloric | 6 mo | IHCLs (primary); ALT, AST, GGT (secondary) | Nonprofit | High |
| Children | ||||||||||||
| Vos, 2009 (65) [United States]; parallel RCT | Children with NAFLD (NR)8 | 10 | NR | 13.0 | (2.1) | Elimination of sugar-containing beverages, fruit juice, and HFCS | Low fructose (−20 g/d fructose intake) (n = 6) compared with low fat (−15 g/d fructose intake) (n = 4)9 | Hypocaloric | 6 mo | ALT, AST (secondary) | Nonprofit and government | High |
1
ALT, alanine aminotransferase; ALKP, alkanine phosphatase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; DNL, de novo lipogenesis; GGT, γ-glutamyl transpeptase; HFCS, high-fructose corn syrup; HFCS-55, high-fructose corn syrup (55% fructose and 45% glucose); IGT, impaired glucose intolerant; IHCL, intrahepatocellular lipid; NR, not reported; pub, publication; RCT, randomized controlled trial; ref, reference; SSB, sugar sweetened beverage.
2
All values are means; ranges in parentheses.
3
All values are means or ranges; BMI z score in parentheses.
4
Study design included fish oil compared with fish oil and fructose compared with fructose. Fish-oil interventions were not included in the analysis.
5
A nonrandomized crossover trial. Ranges of fructose intake reported were as follows: fructose and glucose = for IGT, 45–83 g/d; for control, 45–112 g/d.
6
Fifteen normal-weight and 6 overweight subjects.
7
Ten-week duration included an 8-wk hypercaloric diet and 2-wk isocaloric diet.
8
Seven children (70%) with a confirmatory liver biopsy that showed nonalcoholic steatohepatitis.
9
Low fructose denoted the elimination of sugar-containing beverages, fruit juice, and food items that were high in high-fructose corn syrup. Low fat according to the American Heart Association recommendation.