Currently, there is a worldwide epidemic of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) largely thought to be due to increased dietary caloric intake (1-3). A number of scientists and experts assert that the increased consumption of sugar-sweetened beverages (SSBs) has significantly contributed to these trends, particularly obesity, since the worldwide consumption of sucrose has tripled over the past 50 years (4-6). In the USA, 77% of all calories purchased from 2005-2009 contained sweeteners of which corn syrup, cane sugar, high-fructose corn syrup (HCFS) and fruit juice concentrate were listed as the most commonly used (7). A high SSB consumption reportedly contributes to a 12% increased risk of hypertension, 26% increased risk for T2DM and a 19% increased risk of CVD, suggesting that further research is required regarding dietary sources of simple sugars [mono-(glucose and fructose) and disaccharide (sucrose)] contained in beverages, such as fruit juice (8-10).

A conundrum exists regarding the consumption of fruit juice. The argument in favor of 100% fruit juice as a healthy beverage derives from the fact that Americans of all ages do not meet their daily fruit requirement and 100% fruit juice offers most of the nutrients of whole fruit in a less expensive, more user-friendly form (8,11). In fact, reducing or eliminating 100% fruit juice, and consequently nutrients and fiber contained within, could lead to unintended consequences, such as a reduced daily fruit intake and an increased consumption of less nutritious, calorie-dense beverages, such as soft drinks (12,13). Moreover, numerous fruit juices are produced from exotic ‘superfruits’, such as noni, maqui, acai, goji, pomegranate, etc., due to their complement of beneficial bioactive, e.g., antioxidant, compounds, which can lead to robust health benefits (14,15). However, there is limited published information available on the toxicity profiles of some dietary fruit juices due to their prevalence in the food supply, common use and the general lack of evidence that would support safety concerns. As a result, there seems to be a misconception that fruit juices and smoothies are also low-sugar alternatives to SSBs (4). Although fruit juices may generally be considered safe, chronic consumption, similar to dietary triglycerides (TG), could cause metabolic perturbations, contributing to the risk of developing chronic diseases, such as non-alcoholic fatty liver disease (NAFLD), e.g., liver toxicity and renal dysfunction (16-18).

Fruit juices have been shown to induce mild to moderate adverse effects on typical metabolic biomarkers in different experimental models. For example, in rodent studies, the provision of fruit juice for 48 h significantly and dose-dependently increased liver enzyme, urea and creatinine levels, suggesting both nephrotoxicity and hepatotoxicity (19,20). In another study, the ingestion of pomegranate was associated with the deaths of young cattle without prior clinical signs, although gross subclinical pathological changes indicated hepatotoxicity (21). In a study on noni fruit (Morinda citrifolia), female mice fed fruit extracts for 6 months displayed chronic toxicity with clear hepatocellular necrosis, morphological changes in liver, and death after 3 months (22). In humans, cases of hepatotoxicity have also been reported following the consumption of noni juice. In two human case studies reported by Stadlbauer et al in a single report, individuals developed sub-acute hepatic failure and acute hepatitis following the consumption of 1.5 l juice for 3 weeks and 2 l juice for 3 months, respectively (23). The bottle gourd (Lagenaria siceraria), also known as lauki, ghia or dudhi, prescribed as part of traditional medicine, has been shown to cause numerous signs and symptoms of gastrointestinal and hepatic injury (24). Collectively, there are instances where dietary and/or medicinal fruit juices have increased the risk of hepatotoxicity.

Beverages, such as SSBs may also influence the risk of developing kidney disease (18). In the Jackson Heart Study (n=3,003) a higher consumption of SSBs was shown to elevate the risk of chronic kidney disease (CKD) in a community-based cohort of African-Americans (25). In the Tehran Lipid and Glucose Study (n=1,690), the consumption of >4 servings of SSBs was associated with a higher prevalence and incidence of CKD (26). In the Atherosclerosis Risk in Communities Study (n=15,745) the consumption of 1 SSB/day increased the prevalence of hyperuricemia and CKD with an odds ratio of 2.59 for those consuming >1 SSB/day (17). As mentioned previously, the consumption of star fruit juice also induces kidney degeneration and necrosis compared to the controls, indicating nephrotoxicity (19). In at least one case report, an individual who consumed star fruit developed acute kidney failure requiring dialysis (27). Thus, there are data suggesting the potential for some dietary and/or medicinal fruit juices to cause nephrotoxicity.

Emerging evidence supports the robust complement and activities of bioactive molecules in functional foods, e.g., tart cherries and beverages, such as tart cherry juice (TCJ). The authors have conducted studies previously with TCJ investigating the effects of consumption on inflammatory markers and uric acid in humans, and currently report on the effects of TCJ on body composition or metabolic parameters in at-risk individuals. The present study enlisted overweight and obese individuals at a higher risk for cardiometabolic abnormalities (due to increased adiposity) compared to those with normal body weights (BMI <25.0 kg/m²) to consume 100% TCJ or the placebo beverage for 4 weeks (8 oz/day; 240 ml/day) to determine whether there were any changes in the levels of biomarkers of renal and/or hepatic function.

Few studies have evaluated the associations between the dietary intake of fruit juices, and intermediate biomarkers of cardiometabolic risk, particularly in the context of hepatic and renal function in individuals at-risk for or exhibiting metabolic syndrome (11,28-30). SSBs are consumed globally and have been associated with adverse health outcomes, including weight gain, T2DM and CVD (31-34). Other studies have reported higher systolic blood pressure (hypertension) among those with higher SSB consumption, likely due to associated weight gain (35-37). A recent cohort study (n=13,440 adults ≥45 years) indicated that each additional 355 ml (12 oz) of SSB or fruit juice beverage consumed caused a significant 11 and 24% higher all-cause mortality risk, respectively (38). In the present 10-week 2x2 crossover, randomized, placebo-controlled dietary intervention in overweight and obese participants (BMI ≥25.0 kg/m²), no significant alterations were noted in hepatic or renal function from the start to the end of the study when comparing the TCJ to the placebo group. Dietary intake and physical activity levels were similar among all groups. In addition, no changes were noted in body composition (percentage body fat, lean body mass, etc.) or BMI after 4 weeks of beverage consumption. It was concluded that 100% TCJ does not exacerbate already existing risk factors, viz., elevated fasting blood glucose, in an at-risk (for chronic disease) population or affect adversely hepatic or renal function.

Replacing fruit juice with whole fruits is associated with a lower risk of developing chronic diseases, i.e., T2DM; thus, whole fruit is the preferred dietary means of nutrient consumption from fruits (39). However, there are positive studies supporting the benefits of fruit juice consumption. In children, 100% fruit juice was associated, in part, with reaching daily values of vitamin C, folate and vitamin K intake (12). The consumption of deeply pigmented foods rich in polyphenolic anthocyanins (ACNs), with marked antioxidant and anti-inflammatory activity, has been shown to exert preventive effects against chronic diseases. In a placebo-controlled intervention (n=57), ACN-rich juice consumption for 9 weeks caused DNA protective and antioxidant effects, which were also observed unexpectedly in the placebo group (15). The authors of that study proposed that vitamin C was responsible for the placebo effect. Conversely, the effect of ingestion of different white grape juices (7 µl/g body weight) on biochemical serum profiles and oxidative stress in the liver of adult Wistar rats did not alter biochemical parameters (40). The ingestion of both grape juices elevated glutathione and total antioxidant capacity, with no effects on glucose or uric acid although consumption of 480 ml of antioxidant-rich Concord grape juice per day for 3 months increased insulin resistance and waist circumference in overweight individuals in a different clinical trial (41,42). Indeed, the authors also previously demonstrated that ACN-rich TCJ did not adversely affect blood glucose, but that serum urate (uric acid) was significantly reduced in a population at risk for metabolic syndrome and potentially gouty arthritis (43,44).

There has been increasing interest in ACN-rich tart cherries and their juice due to cumulative myriad health benefits and their purported protection against the development and elaboration of chronic diseases, as reviewed by Kelley et al (45). For example, investigators have demonstrated in numerous studies that tart cherry and/or TCJ clearly reduces potentially damaging oxidative stress, an event thought to be involved in the etiology of several pathologies (46-49). Moreover, given that oxidative stress is closely linked to inflammation, it is not unexpected that TCJ has been shown to significantly reduce undesired inflammation in numerous studies (45,47,50). There is also increasing information supporting an inhibitory role for TCJ in pro-inflammatory gouty arthritis and osteoarthritis, as well as the capacity to reduce exercise-induced pain, soreness and muscle damage often assumed, in large part, to be due to increased oxidative stress (47,51-53). Supportive evidence also suggests that tart cherries and TCJ can modulate risk factors for diabetes and CVD, which are also linked to oxidative stress (54-56). For example, TCJ reduces HbA1C levels, a marker of blood glucose control, in diabetic women with no changes in fasting glucose. Others have demonstrated reductions in both systolic and diastolic blood pressure presumably via, in part, the modulation of nitric oxide levels and vasorelaxation (57,58). Collectively, there is considerable evidence demonstrating the health benefits from tart cherry and TCJ consumption.

There have been several reports that the dietary consumption of some fruit juices exerts adverse effects. For example, in female albino rats fed star fruit juice (dose range of 250-5,000 mg/kg), acute studies suggested the juice was safe up to the highest level. However, after 48 h, liver enzyme (AST, ALT and ALP), urea and creatinine levels were significantly higher in a dose-dependent manner compared to the control (19). Moreover, the authors of that study concluded that the juice of Averrhoa carambola was both nephrotoxic and hepatotoxic in rats after 28 days (4 weeks), a time interval used in the current study. In a different study, rats (n=5) orally treated with juice for 14 days after initial storage of the juice for either 0, 1, or 3 h, liver enzyme (ALT, ALP and AST), urea and serum creatinine levels were once again significantly elevated (19). Damage also occurred at the hepatocellular level with significantly increased serum ALT following the consumption of juice stored for 3 h (20). The ingestion of pomegranates has been associated with the deaths of young cattle without prior clinical signs, although marked weakness and discoloration of mucous membranes were noted in one animal. Gross pathological changes included widespread subcutaneous and serosal hemorrhages with acute periacinar to midzonal hepatocellular necrosis characteristic of toxicity (21). In a study on noni fruit (Morinda citrifolia), commonly used as a functional beverage with medicinal properties, mice were fed water extracts of fruit (two doses each). After 6 months, the study demonstrated that the fruit extract caused chronic toxicity at the highest dose (2 mg/ml water) with clear hepatocellular necrosis, reduced liver length, increased liver enzymes, i.e., AST and reduced albumin and ultimately 40% mortality within 3 months (22). In humans, 2 cases of hepatotoxicity following noni juice consumption were reported by Stadlbauer et al (23). A 29-year-old male with previous toxic hepatitis developed sub-acute hepatic failure (determined via transjugular or percutaneous liver biopsy) following the consumption of 1.5 l noni juice over 3 weeks, mandating urgent liver transplantation. A 62-year-old woman without pre-existing liver disease or dysfunction, developed acute hepatitis following the consumption of 2 l of noni juice over a period of 3 months (23). The bottle gourd (Lagenaria siceraria) also known as lauki, ghia or dudhi is prescribed as part of traditional medicine for T2DM, hypertension, liver diseases, weight loss and other associated problems. However, there have been reports of adverse effects after juice consumption with complaints of abdominal pain, diarrhea, and vomiting (with blood). Endoscopic results displayed profuse gastric bleeding with profound, frequent ulceration of the distal esophagus, stomach and duodenum. Liver enzymes levels were also elevated indicating hepatic toxicity (24). While there are a plethora of beneficial bioactive agents in fruits and consequently fruit juices, there may also be potentially deleterious molecules and/or precursors (59,60). In rodent studies, the provision of juice obtained from Morinda citrifolia (noni) fruit caused significant hepatotoxicity, likely due to the anthraquinones in the seeds and skin, which exhibits quinone reductase inducer activity involved in detoxification of quinones. Studies report that anthraquinone activity is 40-fold more effective than l-sulforaphane, a bioactive organosulfur isothiocyanate in cruciferous vegetables (22,23).

The fructose hypothesis alleges the fructose component common to all major caloric sweeteners and naturally occurring sweetened fruit juice plays a unique and causative role in the increasing rates of CVD, hypertension, T2DM, cancer and NAFLD. One report, however, concludes that fructose intake at normal population levels and patterns does not cause biochemical outcomes substantially different from other dietary sugars (61). Ounce for ounce, some 100% fruit juices may have more sugar than SSBs, but on average, most have a similar energy density and sugar content (62). For example, 250 ml of apple juice typically contains 110 kcal and 26 g of sugar; 250 ml of cola typically contains 105 kcal and 26.5 of sugar. TCJ (240 ml) contains 159 kcal and 33 g of sugar per cup (~16-17 g fructose). An additional consideration is that 100% fruit juices, although nutrient-rich, contain little or no fiber which confers a higher glycemic index to juice.

The amounts of simple sugars and the relative ratios may also be a consideration. In a study comparing the fructose concentration of commonly consumed beverages, 15 beverages had a fructose-glucose ratio exceeding 55% with a mean fructose content of 59% (63). In a study commissioned by the International Society of Beverage Technologists, 80 random beverages known to be sweetened with HFCS-55 were tested. The mean fructose content of these beverages was 55.6% (61). A number of beverages, however, have a fructose content >55% and there may be significant biological differences in response to differing ratios, i.e., 50:50, 60:40, likely due to well-established differences between glucose and fructose metabolism (62,64,65). In short, the excessive supply of fructose to the liver enhances hepatic de novo lipogenesis and increases lipid levels associated with hepatic insulin resistance. A 12-week intervention where 13% of diet energy as fructose was served in the habitual diet of 71 men with abdominal obesity, an increased body weight, liver fat content (steatosis) and post-prandial TG levels were observed. Replacing energy requirement with 10% juice also significantly increased low density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and post-prandial TG levels compared to baseline levels (63). In a 6-month dietary intervention study, subjects consuming one liter of SSB/day exhibited increased TG, cholesterol and liver fat (60). In a previous study conducted in our laboratory, individuals consuming 8 ounces TCJ per day for 4 weeks exhibited a significant increase in erythrocyte sedimentation rate (ESR), an indicator of chronic inflammation, but not the TCJ suggesting the SSB was altering this biochemical parameter (43).

There are several limitations to the current study that may affect the interpretation of the results yet be relevant for the design of future studies. First, the present study was a small pilot study with 10 participants. As a result, the results may not be applicable to larger populations and may not be relevant all races, sexes and/or nationalities. Moreover, the small sample number, although generally considered acceptable for a pilot study, may have been limiting for elaborating potentially significant effects if present. Subsequent studies should aim for larger cohort sizes with more refined inclusion criteria as pilot studies reveal which are most likely amenable to intervention. Another consideration is the length of each arm and the washout period. Chronic consumption of TCJ beyond 4 weeks may lead to different results and although we noted no significant differences due to a carryover effect, e.g., 2-week washout period, this may be too short of an interval for other products. The experimental design, however, was based on other published designs. In the present study, a sweetened, artificially colored fruit punch was used, which arguably may not be as effective as desired for a placebo regarding optimal matching of astringency and the presence of sediment although the colors of the beverages were matched as closely as possible and the caloric and carbohydrate values were similar. Other studies have used fruit-flavored drink mixes, e.g., Kool-Aid, sports beverages, water, synthetic orange-flavored beverages, etc. supporting the placebo selection in the present study (16,47,53). Furthermore, in a previous meta-analysis, Wang et al reported selections for placebo beverages in 12 studies, which included modified sports beverages, synthetic orange-flavored drinks, water, and a generic control drink matched for sugar composition (66).

Important discrepancies between studies, such as the type of fruit juice, dose, duration, study design and measured outcomes contribute to inconsistencies in results between studies and complicates interpretation. As a result, it becomes difficult to provide evidence-based public recommendations regarding the consumption of fruit juices and potential effects on metabolic parameters (63). Given that no association purportedly exists between 100% fruit juice and most risk factors for CVD, including changes in glucose homeostasis, lipid concentrations and blood pressure, the current evidence does not suggest that 100% fruit juice consumption markedly affects the risk of CVD (34,59,67). Evidence exists that 100% fruit juice is associated with major chronic diseases, but the existing body of evidence is too limited to robustly support any expert opinion recommending changing the current guidelines on 100% fruit juice consumption (8). Presently, the World Health Organization (WHO) recommends reducing the intake of free sugars to <10% and ideally <5% of the total daily energy intake (63). More randomized, placebo-controlled clinical trials are required to confirm the health effects of consuming 100% fruit juice and cohort analyses should report both energy-adjusted and energy-unadjusted associations (8,68).