Functional dyspepsia (FD) is defined by the presence of “epigastric symptoms affecting daily life, such as postprandial fullness, early satiation, epigastric pain, and burning, in the absence of underlying organic abnormalities” (1). From a pathophysiological point of view, FD is probably a heterogeneous condition, and disorders of gastric sensorimotor function as well as low-grade inflammation in the duodenum have been implicated in symptom generation (2). The most prevalent pathophysiological finding in FD is impaired gastric accommodation (GA), present in up to 40% of patients, followed by hypersensitivity to gastric distention, which is found in around one-third of the patients. An important subset of about 25% of the patients has delayed gastric emptying (3).
A biological marker, or biomarker, is an indicator of a physiological/pathological state that can be objectively measured to detect differences between groups or the effect of treatments. An ideal biomarker should be characterized by high sensitivity and specificity. It should be simple, easy to use, acceptable to the patient, reproducible, with low intersubject variability and not expensive (4,5). Furthermore, the biomarker should preferably also be able to predict outcome and be correlated with the clinical response of the disease in which it is tested.
For FD, a biomarker, i.e., a diagnostic test that helps diagnosis or predicts response to therapy, is lacking. There is a general consensus that biomarkers are needed to progress the field of motility and functional disorders (4,5). In FD, drink tests (DT) have been proposed as a potential biomarker for the presence and severity of gastric sensorimotor dysfunction. The DT is potentially revealing an integrated assessment of meal-related gastric sensorimotor function in health and FD. Based on these considerations, this review summarizes the current knowledge on the use of DT in patients with FD, to establish whether they could be considered as a biomarker in these conditions.
We conducted a PubMed, Embase, and MEDLINE search for English language articles, reviews, meta-analyses, case series, and randomized controlled trials using the following keywords and their associations: functional dyspepsia, gastroparesis, nutrient tolerance test, nutrient drink test, water load test, nutrient load test, gastric accommodation, and gastric barostat.
We also included preliminary evidence from abstracts belonging to main national and international gastroenterological meetings (e.g., United European Gastroenterology Week, Digestive Disease Week, Neurogastroenterology and Motility meetings, and the Belgian Gastroenterology week). The search was conducted by E. Scarpellini and independently verified by J. Tack.
Types of drink tests
The literature reports on several types of drink tests, either rapid or slow, with or without awareness of quantities ingested by the subject and, probably most relevant, using water or nutrient solutions (Figure 1; see Supplemental Figure 1, http://links.lww.com/AJG/B953).
Results of the rapid water drink test or water load test
The water drink test was originally designed as a provocative assay to study symptom profiles and tolerance of a volume load to the stomach in FD patients. In the first application of the rapid drink test, 24 FD patients and 24 matched healthy volunteers (HV) were asked to drink room temperature noncarbonated water ad libitum over a 5-minute period (Figure 1a), while upper gastrointestinal symptoms and induction of gastric arrhythmias were recorded respectively using symptom rating questionnaires and electrogastrography (6). The article does not mention any sex or age influences. The patients tolerated lower volumes and scored higher symptom scores for fullness, satiety, bloating, and nausea, compared with HV (6). The reproducibility of the water load test was confirmed in this study and also in a preliminary report (6,7).
Boeckxstaens et al. included 25 HV and 42 FD patients drinking aliquots of 100 mL of water every minute until a discomfort score of 5 was reached on a scale from 0 to 5 (Figure 1a) (8). Upper gastrointestinal symptoms were scored after each ingestion of 100 mL and also 1 and 2 hours after the end of the test. Men drank significantly larger water volumes than women, and FD patients tolerated significantly lower volumes and reported greater and more persistent symptoms scores during the water drink test than HV. In similar rapid water drink test studies, Strid et al. found that men ingested significantly higher volumes than women, but age had no effect (9), and Abid et al. studying 42 subjects found that men drank larger volumes than women and the tolerated water volume was also correlated to body mass index (10) (Figure 2a).
Jones et al. evaluated a maximum drinking capacity of water during 5 minutes as well as the maximum tolerance of water ingested in 100-mL aliquots every minute in 73 HV. Both water drink tests were well correlated and well reproducible. Men tended to drink more than women, but the difference did not reach statistical significance. The volume ingested was correlated to age and height, but not to body mass index, and was not correlated to gastric emptying rate (11).
In summary, the rapid water drink test with 100 mL of water every minute until a maximal discomfort score or a maximum drinking capacity of water during 5 minutes is easy to use and seems reproducible, but is influenced by sex and perhaps body mass index. Limitations of the rapid water drink test are the unphysiological approach, the use of a noncaloric challenge, and the awareness of the subject of the volume that is being ingested.
Rapid nutrient drink test
In the study by Boeckxstaens et al., HV and FD patients also drank aliquots of 100 mL of a mixed nutrient drink (Nutridrink; Nutricia Advanced Medical Nutrition, Zoetermeer, the Netherlands) every minute until a maximal discomfort score was reached (Figure 1b) (8). Men drank significantly higher volumes than women (Figure 2a). FD patients tolerated significantly lower volumes and reported greater and more persistent symptoms scores during the drink test vs HV. Those results were like the rapid water drink test, but the tolerated volume of nutrients was significantly less than that of water (8).
Hjelland et al. (12) also had 10 HV and 10 FD patients ingest Nutridrink in 100-mL aliquots every minute until maximal satiation. No significant difference was observed in tolerance of volumes between controls and patients, but the numbers of subjects were low. No sex differences were mentioned. In the study by Abid et al. (10), 42 HV ingested Ensure at a rate of 100 mL/min, with higher volumes tolerated in men. Jones et al. evaluated maximum tolerance of a liquid meal ingested in 5 minutes in 15 HV, compared with maximum drinking capacity of water during 5 minutes and maximum tolerance of water ingested in 100-mL aliquots every minute. They found that both water drink tests were well correlated, but the tolerated volume of the nutrient liquid meal was significantly less than for water (11). In a preliminary report of a study from China, a rapid nutrient drink test (0.6 Cal/mL, fat: 19%, protein: 18%, and carbo: 63%) ingested at a rate of 60 mL/min in 98 FD patients and 14 HV showed significantly lower volume tolerance in the patients (637 mL vs 1,091 mL, P < 0.05 vs controls) (13).
In summary, rapid nutrient drink tests with 100 mL or 60 mL every minute until a maximal discomfort score are easy to use, similar to rapid water drink tests, but their reproducibility is not established and the tolerated volumes are lower than with the water drink test. Limitations of the rapid nutrient drink test are the unphysiological approach and the awareness of the subject of the volume that is being ingested. Moreover, mixed nutrient drinks often have a high caloric and lipid content and may be less palatable to some patients.
Satiety drinking test and slow nutrient drink test
A slow nutrient drinking test was the first drink test to appear in the literature, in a 1998 article addressing the role of impaired GA in FD (14). It was originally conceived to noninvasively assess GA and referred to as “satiety drinking test”. Patients drank a liquid nutrient meal (Nutridrink), dripping from an infusion pump, at a slow constant rate until maximum satiety score (score 5 of 6 from a 0–6 satiety Likert scale) has been reached (Figure 1c) (14,15). This design helps to blind the patient for the amount that has been ingested. The total volume drank is recorded as the primary outcome variable (14–16). In the original report on the satiety drinking test, patients drank significantly less than HV (361 ± 33 vs 1,005 ± 35 mL, P < 0.05). The outcome was related to GA but not to gastric emptying rate (15). Interestingly, one study evaluated the outcome of a slow nutrient and a slow water drinking test, both at a 15-mL/min rate, in 20 FD and 20 HV, showing substantially lower volume tolerance in the patients (17).
Tack et al. (15) studied the impact of changing the caloric density (1.5–2.0 kcal/mL) in the satiety drinking test. Paradoxically, with increasing caloric density, maximum satiety occurred at progressively higher caloric intakes, but the satiety scores according to ingested volume and the ingested volumes at maximum satiety did not differ significantly. These observations show that the satiety drinking test is a volume-driven test, in line with its aim to quantify GA (15).
The reproducibility over 3 sessions of the satiety drinking test was studied in HV (18). A good intrasubject correlation and no significant difference were found between the different visits in terms of volume ingested. Female subjects drank significantly less than male subjects (Figure 2a). Higher ingested volumes were associated with older age in this cohort, and this was attributable to an age effect in men, which was absent in women (18). Interestingly, in children, the satiety drinking test showed an age-dependent rise in girls only (19).
Other studies used a slow nutrient drink test, using drink aliquots and no delivery through a peristaltic pump (Figure 1d). These studies confirmed the higher slow nutrient drink test tolerance in men compared with women (Figure 2a) and a lower tolerance in adolescents compared with adults (20). Using a higher nutrient drinking rate (30 mL/min), Delgado-Aros et al. found a higher nutrient volume tolerance in men compared with women and in overweight or obese subjects (21). Abid et al. (10) also studied a slow nutrient drink test (20 mL/min) in 42 HV. Multiple logistic regressions showed no influence of age, BMI, or sex on nutrient volumes in adult subjects. A study from Japan confirmed the reproducibility of the slow nutrient drink test in healthy male controls (22).
In summary, satiety drink tests (using a peristaltic pump) and slow nutrient drink tests (using drink aliquots) with a rate 15–30 mL/min are easy to use and reproducible, but are influenced by sex and perhaps age. The awareness by the subject of the volume that is being ingested is diminished in the satiety drinking test, where the nutrient mixture is dripping from a pump, with the subject matching the ingestion rate accordingly. Similar as for the rapid nutrient drink test, mixed nutrient drinks often have a high caloric and lipid content and may be less palatable to some patients.
Overall, the literature reports on various types of drink tests using different substrates and different speeds of administration of ingestion. It will be important to simplify and standardize the methodology and reference values for future clinical applications and comparisons between centers.
Outcome of nutrient drink tests in health vs FD
Several variants of the drink tests test have been reported and have confirmed that FD patients ingest significant less volume with a significant faster rise of satiation and other dyspeptic symptoms compared with healthy subjects. This has been observed for the rapid water load test and especially for the satiety drinking test (Figure 3a–c). Taken together, these observations show that lower nutrient volume tolerance in FD patients is a well-reproducible finding across studies.
The most consistent findings with the best separation between health and FD seem to be present in the satiety drinking test studies, which are mainly driven by a single institution (14,15,19,23–25) but which were also confirmed in a secondary care setting (18). The majority of studies used Nutridrink or Ensure. Based on the current literatures, the satiety drinking test is the recommended drink test.
Results of Comparison between drink tests
See supplementary file, http://links.lww.com/AJG/B952.
Results of Relation with pathophysiological mechanisms
See supplementary file, http://links.lww.com/AJG/B952.
Results of Correlation with the symptom pattern in FD
Several variants of the drink tests have confirmed that FD patients ingest significantly lower volumes and that this is associated with induction of higher levels of satiation and more dyspeptic symptoms compared with healthy subjects (6–12,14–16,18,19,23,25–30). The correlation of drink test outcomes with the FD symptom pattern as assessed in symptom severity questionnaires has been analyzed by a number of these groups (Table 1).
In the study by Boeckxstaens et al. (8), the volume tolerated in the rapid water or nutrient challenge tests was inversely correlated with symptom severity profile in the total population including controls, but no correlation was found within the FD patient population. Jones et al. found a negative correlation between the volume of water tolerated and the symptom score as determined by the Nepean dyspepsia index. They also compared the water load test tolerance in ulcer-like and motility-like dyspepsia and found no significant difference (11).
Tack et al. found an inverse correlation between the early satiation score and the volume tolerated in the satiety drinking test (15). Cuomo et al. (24), using the same test, also found a significant inverse correlation with the severity of early satiation and the outcome of the slow nutrient drink test which persisted in multivariate analysis. In a study in 134 healthy subjects, underweight subjects had a lower nutrient volume tolerance in a slow drink test (21). However, in a study in 60 FD patients, van Lelyveld et al. found no correlation between FD symptoms and the outcome of the slow nutrient drink test (33).
In a preliminary report of 26 postprandial distress syndrome patients and 16 HV who ingested Ensure at a rate of 30 mL/min, the maximum tolerated volume was significantly less in patients with severe early satiety compared with those with mild or no early satiation; other symptoms were not associated with maximum tolerated volume (34). The more recent study from Japan, using satiety drinking test, that showed that a nutrient drink test for 30 minutes was able to reproduce symptoms in patients with FD (22).
In summary, the best association between symptoms and drinking tests is found for the satiety drink test, whose outcome is associated with the severity of early satiation in FD.
Results of drink tests in gastroparesis
See supplementary file, http://links.lww.com/AJG/B952.
Pharmacological modulation of nutrient drink tests
See supplementary file, http://links.lww.com/AJG/B952.
Prediction of response to therapy
See supplementary file, http://links.lww.com/AJG/B952.
Drink tests are noninvasive and easy-to-perform techniques to measure the volume of either water or nutrient solutions that can be consumed before feeling satiation or discomfort. However, to be considered a potential biomarker, several aspects beyond practicality should be considered, including sensitivity, specificity, accuracy, and precision when using the test to diagnose disease or to predict the therapeutic response. Based on our literature review, the reproducibility of drink tests in HV seems well established.
In FD patients, both the rapid water drink test and the slow nutrient drink test are well reproducible, and drink test volume tolerance is significantly less compared with HV. Although all tests separate health from FD, this seems most consistently the case in the slow nutrient drink test, whose numerical results also seem most consistent across studies (Figure 3). Two aspects may contribute to the good performance of this test compared with the rapid water or nutrient load test. First of all, because of the nature of the satiety drink test as it usually applied, the subject is not directly aware of the volume consumed because it is slowly dripping from a peristaltic pump and the patient or volunteer is asked to continue drinking at this rate. This approach contrasts with the rapid tests where subjects are asked to drink aliquots, usually of 100 mL, so they are conscious of the ingested volume. The second strength is the underlying physiological mechanism because most studies found correlations between slow nutrient drink test volume tolerance and GA. Impaired GA is the most prevalent pathophysiological abnormality found in FD (1,3,31,32,35), and a test reflecting this function is therefore more likely to show consistent change from controls.
A somewhat surprising observation is that the tolerated drink test volume seems lowest with the slow nutrient drink test. This is probably in line with GA as the physiological basis underlying this test. First, GA of the fundus and proximal stomach in a healthy volunteer takes up to 10 minutes after a test meal to become maximal (8). The rapid water or nutrient challenge tests are finished well before this timeline and hence are unlikely to reflect GA. Second, duodenal nutrient exposure is a determinant of GA and duodenal feedback contributes to determining the size of GA and hence gastric volume capacity (36,37). This feedback, involving release of satiety signaling hormones (38), and its impact on GA are likely key factors determining the smaller total volume tolerance associated with the satiety drinking test. Duodenal feedback is unlikely to contribute majorly to volume tolerance of rapid drink tests, especially the water load test.
Based on our findings, the slow nutrient drink test seems able to distinguish FD from health, but it has not been widely applied in clinical practice. Whether the test can distinguish FD from organic causes of dyspepsia has not been studied to date, and this would be required to established any diagnostic value of the satiety drink test. On the other hand, a diagnosis of FD is usually not challenging in clinical practice, so the need for such a diagnostic test in FD is less obvious.
In addition to their contribution to understanding underlying pathophysiology, slow nutrient tests may have a role in determining choices of pharmacological treatments in FD. Several pharmacological approaches are available to alter gastric sensorimotor function and therefore alter symptom severity and expression in FD and GP. Some agents enhance gastric contractility while others target GA or visceral sensitivity. Current management approaches are often based on trial and error, where agents with different properties are sequentially applied based on availability, cost, and side-effect profile (1,3,31,32,35,39). Several studies have established concordance between effects of pharmacological agents on GA and their effects on slow nutrient drink test tolerance. Only a handful of data are available to suggest predictive value of the drink test on the outcome of therapies (40,41), but further studies are definitely worth pursuing. We would recommend considering inclusion of the slow nutrient drink test in phase II studies in FD to assess their ability to predict response to therapies, as has already been done for acotiamide, nortriptyline, and TAK-906 (40–42). The use of drink test in pharmacological studies would also benefit from further standardization; caloric content and distribution and drinking rate for the tests have not been established. Nutridrink and Ensure (Abbot Nutrition), currently used for satiety drinking tests, have a high caloric and lipid content and may be less palatable to some patients. Last but not least, a number of studies could not confirm the relationship of the slow nutrient drink test to symptoms, mechanisms, or treatment outcomes, indicating that further studies are surely needed to confirm its value (26,33,42–44).
In summary, a satiety drinking test has the potential to be considered not only a potential diagnostic biomarker but also a possibly predictive biomarker for treatment outcome. It is noninvasive, well tolerated, and reproducible and can help to identify impaired GA, quantify pharmacological influences, and possibly indicate the likelihood of benefiting from a specific therapy. Because of their simplicity, drink tests could be implemented in clinical care as one of the tools in secondary care or tertiary medical centers and maybe even in primary care. This will require support from additional studies, first in the evaluation of patients with an equivocal diagnosis of FD and in patient with symptoms that persist despite first-line therapeutic measures. The satiety drinking test seems most appropriate, given its link with impaired GA, but it is somewhat more time-consuming. The rapid water drink test and rapid nutrient drink test can be an alternative choices, but more studies are needed to investigate whether these are truly markers of visceral sensitivity. If further validated, drink tests have the potential, combined with other clinical factors, to personalize the clinical management of FD.
CONFLICTS OF INTEREST
Guarantor of the article: Jan Tack, MD, PhD.
Specific author contributions: E.S. and K.V.d.H.: revised the literature and wrote the article draft. J.T.: critically revised the article. J.S. and I.H.: prepared the figures. E.C. and F.C.: prepared the included table.
Financial support: Supported by Methusalem grant METH/14/05 from KU Leuven to J. Tack.
Potential competing interests: J. Tack has given scientific advice to AlfaWassermann, Allergan, Christian Hansen, Danone, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neutec, Novartis, Noventure, Nutricia, Shionogi, Shire, Takeda, Theravance, Tramedico, Truvion, Tsumura, Zealand, and Zeria pharmaceuticals and has served on the speaker bureau for Abbott, Allergan, AstraZeneca, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Truvion, and Zeria.
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