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Original Articles: Gastroenterology

Impaired Gastric Emptying and Small Bowel Transit in Children With Mitochondrial Disorders

Bhardwaj, Jatinder*; Wan, David Q.; Koenig, Mary Kay; Liu, Yuying*; Hashmi, Syed Shahrukh*; Rhoads, Jon Marc*

Author Information
Journal of Pediatric Gastroenterology and Nutrition: August 2012 - Volume 55 - Issue 2 - p 194-199
doi: 10.1097/MPG.0b013e3182514805

Mitochondrial disorders (MDs) arise when dysfunction of the mitochondria causes impaired energy production in cells. The first MD was described by Luft in 1959 (1), and the term “mitochondrial disorder” has evolved to describe genetic defects in the function of the mitochondrial electron transport chain (2). Initial descriptions showed MDs as primarily neuromuscular diseases, and MDs were thought to arise exclusively from mutations in the mitochondrial DNA. It is now well known that defects in oxidative phosphorylation can be caused by mutations in either the nuclear or mitochondrial DNA and that these disorders affect multiple organ systems (3). Gastrointestinal (GI) symptoms are among the most prevalent. Constipation and gastroesophageal reflux are seen in many patients with MD; altered GI motility is often attributed as being responsible for these symptoms (3). There are no proven treatment strategies, and the present management is nonspecific.

Prospective trials in children with MD evaluating GI function have not been undertaken. A retrospective case series reported that 6 children with MD had GI disease, including gastric dysmotility, presenting in the neonatal period (4). Another retrospective series described 20 of 36 subjects with MD as having GI dysfunction. Failure to thrive was seen in 14 subjects, with a requirement for gastrostomy feeding in 2 (5). Dysphagia was seen in 4 subjects, intestinal pseudoobstruction in 3, impaired liver function in 3, cyclic vomiting in 2, and chronic diarrhea in 1. One child required colectomy (5). A third retrospective study found a high prevalence of MD in patients who presented with chronic intestinal pseudoobstruction (6). Lastly, researchers reported that the 3243A > G mtDNA mutation was detected in the stomach of 4 patients with gastric symptoms (3 with abnormal electrogastrography) (7). The study concluded that the gastric dysmotility was associated with accumulation of the 3243A > G mitochondrial DNA mutation in specific regions of the stomach (body more often than antrum).

Few studies have addressed GI function in children with MD. Questions that frequently arise include the frequency and severity of gastric emptying (GE) delay and/or prolonged intestinal transit time (ITT). We undertook a prospective clinical trial at our university center in a cohort of subjects with MD to assess these concerns.


All eligible patients with MD studied at the University of Texas Mitochondrial Clinic ages 3 to 18 years were invited to participate. Institutional review board approval was obtained by the University of Texas Medical School at Houston's committee for the protection of human subjects. The study was conducted in the nuclear medicine suite of our children's hospital. All of the eligible candidates carried a diagnosis of “definite” or “probable” MD based on the modified Walker criteria set forth by Bernier in 2002 (8) (supplemental digital content Table 1, The parents of all of the subjects provided written informed consent for the study following an explanation by the research team of the inherent risks and benefits involved in the nuclear medicine procedure. Subjects 6 years or older gave informed assent/consent before the study.

Inclusion criteria included one or more of the following GI symptoms: abdominal pain (AP), vomiting, constipation (defined as hard bowel movements at least once per week), diarrhea, and gastroesophageal reflux. AP was self-scored by study subjects using a visual analog scale, rated from 0 (no pain) to 10 (the most pain possible). Only verbal subjects were included. The distribution of GI symptoms in our population is shown in Figure 1.

Distribution of gastrointestinal symptoms among study cohort of children with mitochondrial disorders depicted in percentages. Study cohort (n = 26) included those with abdominal pain (AP; n = 12), gastroesophageal reflux (GER; n = 11), constipation (Const; n = 10), vomiting (n = 2), and diarrhea (n = 1).

Exclusion criteria included the presence of another GI disorder such as inflammatory bowel disease, celiac disease, or autoimmune enteropathy (ruled out by the treating physician by performing necessary biochemical workup and endoscopic evaluation with biopsies, if required); the need for parenteral nutrition; or a requirement for enteral feeding by a nasogastric, gastrostomy, or gastrojejunal tube within the last 6 weeks. Subjects with a history of disordered glucose metabolism, diabetes, or hypoglycemia and children who underwent a nuclear GE scan within the proceeding 1 year were also excluded. Pregnant females were excluded; all of the female subjects 11 years of age or older underwent a urine pregnancy test before enrollment.

Fifty-eight subjects who met the modified Walker criteria (8) for a diagnosis of MD were screened for initial evaluation. Of these, 32 did not meet enrollment criteria: 14 were receiving mechanical feeding via gastrostomy or gastrojejunal feeding tubes, 1 was receiving chronic parenteral nutrition, 6 reported no GI symptoms, and 5 had nuclear medicine testing performed within the last year. Parents of 2 subjects declined to participate, and 4 subjects were unable to enroll because they resided in a remote location. A total of 26 eligible subjects were enrolled.

After an overnight fast, subjects consumed an age-appropriate solid (scrambled eggs, toasted bread, juice) or semisolid meal (milkshake) labeled with radioactive technetium 99m sulfur colloid (Tc99SC) on the day of the scintigraphy/nuclear medicine testing. Pediatric radiotracer dose calculation was based on the body surface area: (body surface area/1.7) × 0.7 mCi. Subjects were encouraged to consume the radiolabeled meal within 10 minutes. Immediately thereafter, imaging was performed using large field-of-view γ-camera with low-energy, parallel-hole collimator. Serial anterior and posterior images of the abdomen were obtained using a 10% energy window over a 140-KeV Tc photopeak. The images were captured at 1-minute intervals for 90 minutes. The rate at which radioactivity left the stomach was calculated based on the geometric mean. To evaluate the ITT, anterior and posterior emission images and cobalt-60 transmission images of the abdomen and pelvis were acquired 4 and 6 hours after radiolabeled meal consumption. Approximate mouth-to-colon transit time was defined as ITT. Between imaging sessions subjects were permitted to sit and walk, although they avoided strenuous activity. Data on all of the study subjects were electronically stored for further analysis.

Depending on the type of meal consumed, delayed GE was reported as >90 minutes for half of the stomach to empty for solids, 60 minutes for semisolids, and 40 minutes for liquid meals. Additionally, individuals with borderline delayed GE (GE time of 80–90 minutes) were considered to be “delayed GE” if the lag time was >20 minutes. For ITT, any time <4 hours for the radioisotope to reach the cecum was reported as normal ITT, whereas time between 4 to 6 hours was reported as moderately prolonged and >6 hours as severely prolonged.

Repeat scintigraphy was undertaken wherever possible in the subjects with delayed GE after treatment with prokinetic medications for 6 to 8 weeks. The goal of repeating the study was to determine whether delayed GE time in such patients would improve upon treatment. Only subjects with delayed GE times were treated with a prokinetic. Subjects with prolonged ITT but normal GE time were not treated with prokinetic medications. First-line therapy was metoclopramide at 0.2 mg/kg administered 20 to 30 minutes before meals 3 times per day for 6 to 8 weeks. Subjects who had a contraindication for metoclopramide or those whose parents refused metoclopramide were prescribed bethanechol at the same dose. Azithromycin was prescribed in an unusual situation in which a patient was not willing to take either of these 2 medications. Despite our best efforts, repeat study could not be performed in half of the subjects with initial delayed GE times.

Subjects who were receiving any prokinetic drug treatment from before the initial study for any reason had their medications stopped for 48 hours before the day of the initial scintigraphy. The prokinetic(s) were restarted after the completion of the study, but these subjects did not undergo a repeat scintigraphy. A child who was enrolled initially with diarrhea as the only presenting symptom did not receive treatment with a prokinetic drug or undergo a repeat scintigraphy study (see Results section). The patient was not excluded because diarrhea can be a manifestation of the altered GI motility, for example, small intestinal bacterial overgrowth.

Statistical Analysis

Statistical analysis was performed using GraphPad Prism 4.0 software (GraphPad Software, San Diego, CA). The results are expressed as median and mean ± standard error.



Twenty-six subjects (20 boys, 6 girls) fulfilled the eligibility criteria and were enrolled in the study. Mean age was 7.7 years (range 3–16 years). Using the modified Walker criteria (8), 20 of the 26 study subjects had definite MD (77%), whereas 6 (23%) were diagnosed as having probable MD (Table 1) (supplemental digital content Tables 1 and 2,

Descriptive characteristics of the study cohort

GE Time

Eighteen of the 26 subjects (69%) had prolonged GE time (Table 1). A total of 10 subjects had abnormal lag phase (LP), and of those, 3 had prolonged LP only, although their GE times were normal. All of the subjects consumed a solid radiolabeled meal, except subject 6, who consumed a semisolid meal for the study. The median GE time was 99 minutes (range 45–345) (Fig. 2).

Distribution of gastric emptying (GE) times in patients with mitochondrial disorders. Number of subjects (Y axis) versus GE times in minutes (X axis). The reference normal or abnormal GE time has been indicated along the X axis.


Overall, ITT was prolonged in 12 subjects (46%). Among those subjects it was moderately prolonged in 4 (33%), and severely prolonged in 8 (66%) (Table 1).

Repeat Scintigraphy

Of the 18 subjects with prolonged GE time, repeat scintigraphy could not be performed in 8 patients. Five subjects declined prokinetics. One subject's only presenting symptom was diarrhea. One was receiving metoclopramide and another one was receiving bethanechol before the original scintigraphic study. A total of 9 subjects underwent repeat scintigraphy after treatment with prokinetics. No adverse effects were reported from the use of the prokinetic agents. GE time continued to be prolonged in 6 of the 9 subjects (66%), with a median GE time of 107 minutes (range 80–345) before prokinetic treatment for these subjects and 128 minutes (range 60–360) after prokinetic treatment (P = 0.86) (Fig. 3).

Comparison of GE time of the subjects who underwent repeat study. Nine subjects underwent repeat study. Median GE time was 107 minutes during the first and 128 minutes during the second study (P = 0.8).

Repeat ITT

Of the 9 children who underwent repeat studies after prokinetic drug treatment, ITT normalized in 2 subjects, continued to be prolonged in 3 subjects, remained normal in 2 subjects, and became paradoxically prolonged in 1 subject with a previously normal ITT (Table 1). One subject did not undergo the full 6-hour repeat study (according to parents’ wishes).

Metoclopramide Group (n = 5)

GE time continued to be delayed or worsened after treatment in 3 subjects, whereas it normalized in 2 subjects. ITT continued to be delayed in 3 subjects, normalized in 1 subject, and continued to remain normal in 1 other subject.

Bethanechol Group (n = 3)

One subject's gastric LP normalized from 30 to 16 minutes, whereas in 2 others the GE time became prolonged (80–110 minutes in one and 107–177 minutes in the other) (Table 1). ITT paradoxically became prolonged from normal in 1 subject and remained normal in 1 subject (Table 1). One other subject did not complete the full 6-hour study.

Azithromycin Group (n = 1)

This subject's GE time continued to be abnormal, whereas his ITT became normal.


AP was the most common of all of the presenting GI symptoms (n = 14) (Fig. 1) (supplemental digital content Table 2, The abdominal pain index was scored via self-report in 10 of the 14 subjects using the 10-point visual analog scale. AP could not be scored in 3 subjects because they were not able to assign a numerical value to the pain. One other subject did not score the pain for personal reasons. Among those reporting AP, the mean AP score of 4.8 before treatment remained essentially the same at 5.6 after prokinetic drug treatment in the subjects undergoing repeat study.

Correlation Between GE Time and AP Score

Univariable and multivariable regression models and GE time by AP score did not yield a statistically significant correlation between GE time and AP score.

Nutritional Status and BMI

Many of the subjects were overweight; median BMI was 67.5 percentile (range 1–99). Sixteen of the 26 subjects (61%) were above the 50th percentile for age-adjusted BMI, and 8 of those (30%) were above the 95th percentile (Fig. 4). Interestingly, 100% of the 3 underweight subjects had abnormal GE times, whereas 57% (n = 8) of normal-weight and 66% (n = 6) of overweight subjects had abnormal GE times. Although the median GE time was uniformly abnormal in the 3 subjects classified as being underweight (BMI <5th percentile), the difference was not statistically significant.

Correlation between gastric emptying times (x axis) and body mass index (BMI) (y axis). Underweight children had increased gastric emptying times compared with overweight subjects, although the difference was not statistically significant.

Comparison Between Definite Versus Probable Mitochondrial Groups

There were 6 subjects with probable MD, and 5 (83%) of those had delayed GE times. In comparison, 12 (60%) of the 20 subjects with definite MD had delayed GE times (P = 0.38). ITT was prolonged in 3 (50%) subjects with probable MD and 9 (45%) with definite MD (P = 0.55). In summary, the strength of diagnosis did not affect the likelihood of having delayed gastric or intestinal transit.

Complications and Subsequent Follow-up

There was a single complication related to gastroparesis. Subject 8 reported persistent AP approximately 5 months after repeat scintigraphy (although GE time showed normalization from 167 to 60 minutes). An elective computerized tomogram of the abdomen ordered showed a bezoar in the stomach; a phytobezoar was endoscopically retrieved without complications. This patient continued to have severe pain and went on to require gastrojejunal feedings.

Another patient (subject no. 25) with anorexia developed malnutrition and went on to require gastrojejunal feedings. This patient subsequently received gastric pacing at another institution, which resulted in increased oral intake, weight gain, and reduced enteral feeding requirement.


Many children with MD are intolerant of oral feeding and require mechanical feeding. Our study is the first prospective study of GE and ITT in a cohort of children with MD not requiring tube feeding. We chose to study subjects who had only mild-to-moderate GI symptoms. Subjects with severe GI symptoms such as those with intestinal pseudo-obstruction requiring tube feedings or receiving parenteral nutrition were intentionally excluded because GI motility is known to be abnormal in such patients. A symptom score was assessed wherever applicable before and after treatment. Contrary to the popular notion that mitochondrial patients are malnourished, we found that approximately one-third of the subjects with MD were obese (BMI >95th percentile) and most had prolonged GE or ITT.

Scintigraphy of the GI tract is routinely performed using various indigestible radiolabeled markers (technetium 99 for solid or semisolid meals, and indium-111 for liquid meals) (9). Tc99mSC was used in the present study due to its lower cost, shorter half-life (6 hours for Tc-99 vs 2.8 days for In-111) (10,11), and because our study recruits thrived primarily on a solid or semisolid diet. The caloric content (12,13) and the nature of the ingested meal are the major determinants of GE. Among solids, foods rich in carbohydrates empty most rapidly (13), protein-rich foods empty more slowly (14), and predominantly fatty meals empty the slowest (15,16).

The triturating or milling phase, during which time solid emptying does not occur, is known as the LP (17), which correlates with grinding of the food in the gastric antrum until it reaches a particle size of 1 to 2 mm. LP is not seen after liquid or sometimes even after semisolid or solid meals in healthy subjects, because the stomach may empty soon after the meal in a relatively linear manner (18). Under physiological conditions, the normal LP (as measured by appearance of detectable proximal small intestine activity) is 8 to 15 minutes for solids (19) and is often referenced at <20 minutes in healthy humans (a value used in the present study). Based on above references, anyone whose LP was >20 minutes was classified as having delayed GE in our study (even though their GET was normal), although the routine standardized GE measurements are defined based on the gastric half-emptying time as compared with LP per se. Ten subjects had delayed LP, based on this criterion in our study. We used 90 minutes as the reference solid GE time because this value is most commonly used as half-emptying time for healthy adults, and pediatric studies show similar values.

A case-control study undertaken in newborn babies previously reported a GE time of 87 ± 29 minutes in healthy infants fed 50 mL milk labeled with indium microcolloid (20), whereas another study reported the half GE time to be 78 minutes in term infants fed expressed breast milk (9). Because our children were not infants, we used the 90-minute criterion for solid emptying and found that the majority of children in our study had gastroparesis. This abnormality was associated in many cases with AP and/or vomiting but, as mentioned, was not associated with malnutrition.

ITTs have also not been extensively studied in children, although 4 hours is most commonly used as the reference. In 1 report of 680 adult small bowel barium studies during a 2-year period, the ITT was reported to be ≤2 hours in 83% of cases, with a mean ITT of 84 minutes (21). Another study measured the normal ITT in 10 healthy volunteers with no history of GI disease using Tc-99 mixed in charcoal, delivered by a gastric acid–resistant enteric capsule. The mean transit time was 140 ± 76.5 minutes (22). Read et al (23) reported the mean cecal arrival time to be 2.8 ± 1.5 hours. We used a conservative value of 4 hours as the reference “normal” time for contrast to be identified in the cecum. ITT studies in our children confirmed a significant motility disturbance by showing markedly delayed orocecal transit in 46% of the children with MD.

GE and ITT were included and behaved as independent variables with no relation seen among the 2. We saw subjects with delayed GE times with normal small bowel transit time and vice versa. There was no propensity or relation seen of abnormal results associated with a subject having a definite or probable MD.

One provocative finding of the present study was that so many overweight children with MD had gastroparesis. In fact, all 9 overweight children (BMI >85th percentile) were also obese (BMI >95th percentile), and of these, 6 had abnormal GE time, as defined in our study (delayed GE or borderline GE in the presence of delayed LP). One may intuitively predict that those children with more food remaining in the stomach would consume less. Actually, recent studies in obese individuals have shown that delayed emptying is not rare in this population, and stimulating GE may reduce energy intake. Torra et al showed in a randomized, controlled trial of obese adults (OBERYTH trial) that pharmacological manipulation of GE by giving intravenous erythromycin produced a 10% increase in GE time that was accompanied by a decrease in energy intake of 135 cal (24). One may speculate additionally that these subjects have a decreased metabolic rate and hence decreased energy requirements.

The limitations of our study include the lack of standardized normal values for GE and ITT in the pediatric population, the inability to repeat scintigraphy in all of the subjects with delayed GE time, and the inability to treat all of the subjects with delayed GE with the same prokinetic agent. Despite these limitations, to our knowledge, ours is the first prospective trial investigating GE and ITT in pediatric subjects with MD. Our study validates the previous retrospective reports citing GI dysfunction in mitochondrial patients (4,5) and highlights that the majority of mitochondrial patients with mild GI symptoms show delayed GE times and/or prolonged ITT. Although not proving causality, we observed that many MD subjects with AP had delayed GE. In fact, gastric LP was also found to be prolonged in many subjects with either AP or vomiting as their presenting GI symptom. Our study also suggests that MD patients’ GI symptoms are refractory to treatment with the conventional prokinetic medications, suggesting that new pharmacological therapies need to be developed for this cohort of patients. In our opinion, nuclear medicine testing of the GI tract is of relatively high yield in patients with MD, as opposed to other investigations such as invasive endoscopy, sonographic, and/or plain radiologic imaging. Future investigations need to be undertaken to improve treatment of GI symptoms in this population.


We thank the Memorial Hermann Foundation, including the director of the clinical research unit, Cheryl Chanaud, PhD, and Craig Cordola, CEO of the Children's Memorial Hermann Hospital, Houston, TX, for providing the resources to undertake the present study. We thank the nuclear medicine division for supporting this research study.


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azithromycin; bethanochol; delayed gastric emptying time; metoclopramide; mitochondrial disorder; prokinetics; small bowel transit time/intestinal transit time

Supplemental Digital Content

© 2012 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,