Urinary glutamine/glutamate ratio as a potential biomarker of pediatric chronic intestinal pseudo-obstruction

Dear Editor,

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder of intestinal motility characterized by severe and disabling repetitive episodes or continuous symptoms and signs of bowel obstruction, in the absence of a fixed, lumen-occluding lesion. Its prevalence is about 1 in 40,000 to 100,000 live births [1, 2], and the overall mortality rate has been reported to be between 10 and 32% [3]. The quality of life for patients with CIPO is poor due to persistent symptoms, frequent emergency room visits and hospitalizations, and the need for nutrition support. A large proportion of patients become malnourished with up to one-third of adults and 80% of children requiring long-term home parenteral nutrition. The clinical picture tends to be dominated by abdominal distention (98%), vomiting (91%; bilious in 80%), abdominal pain (58–70%), failure to thrive (62%), diarrhea (31–42%), constipation (42–77%), feeding intolerance (39%), and urinary symptoms (11%), which are particularly severe during episodes of pseudo-obstruction [4]. Notably, pseudo-obstruction is a term used to define a heterogeneous group of neuromuscular disorders, which can be further classified into three major types: neuropathies, myopathies and mesenchymopathies, based on the histological underlying abnormalities of enteric neurons, smooth muscle cells and interstitial cells of Cajal (ICC), respectively. However, no matter the etiology, the end result presents markedly compromised peristalsis within the gastrointestinal (GI) tract. Thus, CIPO should be considered as a description of symptoms rather than a true disease.

The first challenge for physicians dealing with these patients is to establish a firm diagnosis from those above-mentioned symptoms, which are nonspecific and similar to the clinical manifestations of other gastrointestinal diseases like short bowel syndrome (SBS). Misdiagnosis or a delay in diagnosis typically result in the disease going unrecognized for long periods, which means that patients often undergo repeated and potentially dangerous diagnostic tests and treatments. Currently, a stepwise approach has been used to make the diagnosis of CIPO, including pertinent laboratory studies, plain films of the abdomen, GI transit measurements, and specialized tests of GI motility [5]. However, the diagnosis of CIPO can be elusive for a number of reasons: 1) symptoms typically evolve slowly over a number of years rather than develop at once; 2) initial diagnostic tests (ie, endoscopy and abdominal ultrasound) are usually normal; 3) Biologic markers for CIPO are not available. Therefore, it is desirable to identify and establish new laboratory diagnostic markers for CIPO that are reliable and easily accessible.

By liquid chromatography/mass spectrometry (LC/MS)-based urinary amino acid metabolomic profiling, we have identified the ratio of the urinary glutamine (Gln) and glutamate (Glu) as a promising biomarker for aiding distinguish suspected CIPO cases and simple SBS cases. Here, SBS patients were enrolled for the following reasons: 1) Up to 80% of the pediatric patients who develop symptoms suggestive of intestinal failure (IF) are SBS patients in our department. Therefore, in order to effectively screen out potential CIPO patients from the whole group of IF patients, SBS patients would be an appropriate control group because of its good representativeness. 2) Normally, SBS patients do not have obstruction, however, those with poor enteral feeding tolerance may have such obstruction-like symptoms as abdominal distention, vomiting and abdominal pain, especially after receiving inappropriate enteral nutrition. On the other hand, severe cases may exist who combine short bowel with dysmotility. In addition to screening out potential CIPO patients, our results may also aid distinguish whether the obstruction-like symptoms in SBS patients are attributed to dysmotility or simply enteral feeding intolerance.

In the current study, though the exact mechanism needs to be further investigated, here, we propose an “energy-based acidosis” hypothesis. Given that urinary excretion of glutamine and glutamate is sensitive to environmental pH, renal catabolism of glutamine is accelerated during chronic metabolic acidosis, leading to increased excretion of glutamate and decreased excretion of glutamine. As a result, the ratio of the urinary glutamine and glutamate is decreased, compared to the normal [6]. We hypothesized that patients with CIPO may represent chronic acidosis due to the compromised energy metabolism in intestinal smooth muscle cells, in which decreased aerobic oxidation along with increased anaerobic glycolysis may lead to the accumulation of acidic metabolites. These acidic metabolites may chronically affect the overall body condition, and therefore, for CIPO patients, this ratio not only reflects the severity of acidosis, but also substantially reflects the severity of compromised energy metabolism within the GI tract.

Since SBS patients do not represent severe disorders of energy metabolism while CIPO patients do, we hypothesize that the urinary Gln/Glu ratio may serve as a potential diagnostic biomarker for CIPO.