Endoscopic full-thickness gastric biopsy: Ready for prime time?

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Introduction

Gastroparesis is a syndrome of delayed gastric emptying in the absence of mechanical obstruction. Common symptoms of the disease include early satiety, postprandial fullness, nausea, vomiting, bloating and upper abdominal pain . The most common etiologies for gastroparesis are idiopathic, diabetic and surgical, whereas less common causes include parkinsonism, amyloidosis, paraneoplastic and scleroderma . Gastroparesis is primarily a neuropathic condition, whether it is autonomic neuropathy (idiopathic or diabetic) or loss of extrinsic neural control (vagal nerve injury, parkinsonism, amyloidosis). Less commonly the underlying pathophysiology could be infiltration or atrophy of the muscle layer as seen in malignancies, scleroderma as well as amyloidosis . Gastroparesis is associated with decreased patients’ quality of life, increased health-care costs; including office visits, emergency room visits, hospitalizations; as well as negative health outcomes . The number of gastroparesis-related hospitalizations has been increasing in the United States. Moreover, economic impact of gastroparesis-related hospitalizations has been raising with estimated of more than 200 million dollars in 2004 .

The pathophysiology of gastroparesis is poorly understood. Data suggest that there are distinct histologic subsets of gastroparesis. The gastric nervous system cannot be evaluated with traditional endoscopic punch biopsy as it usually misses submucosal neuromuscular structures and does not capture muscularis propria (MP). Traditionally, diagnostic histopathological evaluation of gastrointestinal (GI) motility disorders was only possible with a surgical biopsy. However, a surgical full-thickness bowel biopsy is associated with some significant morbidity. In a study by Knowles et al, 124 patients with clinico-physiological diagnoses of chronic intestinal pseudo-obstruction underwent laparoscopy and full-thickness bowel biopsy. Surgery-related morbidity such as bleeding and obstructive symptoms occurred in 11% of patients. Conversion to an open operation occurred in 2% . Apart from short-term adverse events, any surgical procedure is a risk factor for long-term complications, such as intraabdominal adhesions with consequent pain and/or bowel obstruction. Although specific diagnostic yield was high, particularly for jejunal biopsies (89%), due to the invasive nature of the surgical full-thickness biopsy and its potential complications, it has not gained broad utilization .

Recent advances in endoscopic technology have now made acquisition of deep tissue or full-thickness biopsies possible. This chapter will review the current techniques for full-thickness or deep gastric biopsies, and discuss practicalities regarding whether this approach should be implemented in clinical practice.

Gastric nervous system

The enteric nervous system contains 200–600 million neurons that are distributed in small ganglia and are mainly found in two plexuses: the myenteric (or Auerbach’s) and submucosal (or Meissner’s) plexus. The myenteric plexus lies between the longitudinal and circular muscle and extends the entire length of the gut. The submucosal plexus is located between the circular muscle layer and the muscularis mucosa, and is best developed in the small intestine, but not in the stomach or esophagus .

One important participant of gastrointestinal autonomy are the nonneural cells called interstitial cells of Cajal (ICC), which serve as electrical pacemakers and mediators of enteric neurotransmission . A gastric pacemaker area is localized at the proximal part of the great curvature and generates a slow-wave basal rhythm with a frequency of three cycles per minute, which spreads distally and determines the frequency of gastric contractions . This area was not significantly affected by a proximal gastric vagotomy and when transected from the gastric corpus, a new pacemaker appeared in the distal stomach with a slower frequency .

Gastrointestinal autonomic rhythmicity is thought to be comprised from ICC as well as the myenteric plexus and submucosal plexus. These structures are widely distributed in the gastrointestinal tract. ICC generate spontaneous pacemaker currents that drive the mechanical activities of smooth muscle cells . These cells have been referred to as pacemakers in gastrointestinal muscles . Based on their morphological features and location, ICC are divided into intermuscular (between the circular and longitudinal muscle layers), intramuscular (within the muscle layers), deep muscular plexus (between inner and outer parts of the circular muscle), submucosal surface of the circular muscle and subserosal layer . Different types of ICC are thought to carry out different roles, however regardless of their function type, a decrease in ICC density has been found in patients with gastrointestinal motility disorders including gastroparesis . In addition, preservation of ICC has been associated with a better response to gastric electrical stimulation in patients with gastroparesis and their depletion has been seen in patients with greater symptomatology even after three months of gastric electrical stimulation .

Pathophysiology of gastroparesis

Pathophysiological changes in gastroparesis are a complex group of changes incited by alterations in various mechanisms. Gastric emptying is affected by less frequent contractions, antroduodenal incoordination and pyloric spasm . Along with discordance of function, disturbances of gastric compliance (increased or decreased ) have been reported as potential contributors to the symptomatology. Such disturbance of synchrony is attributed to loss of coordination between smooth muscle, autonomic nerves and ICC, all of which separately or in combination, are affected by an underlying condition. ICC have since gained broad recognition and subjects with diabetic and non-diabetic gastroparesis have been found to have a reduced number . In addition, several studies have demonstrated subcellular changes in animals with a decrease in nitric oxide-containing nerves , which was later seen in human studies along with a deficiency of ICC and substance P .

Initial studies of gastric tissue conducted on cadaveric stomachs using silver staining demonstrated normal histology with a normal myenteric plexus, abdominal vagus and branches in both affected subjects and the control group . Since then, more specific and sophisticated immunohistochemical staining techniques have been developed and implemented for the enteric nervous system.

Full-thickness gastric biopsies obtained by the Gastroparesis Clinical Research Consortium, revealed that both idiopathic and diabetic gastroparetic stomachs had cellular abnormalities in 83% of cases . The most common abnormality was a decrease in ICC. Residual ICC were often observed as not in contact with nerve endings and only rarely with smooth muscle cells, or with other ICC. The second most common abnormality was phenotypic changes in immune cells in the muscularis propria or an increase in the number of immune cells. Notably these changes were seen in both idiopathic and diabetic patients. Other findings in this study included decreased expression of neuronal marker PGP9.5 suggesting a decrease in nerve fibers. Nitric oxide synthase expression, however was found to be decreased more in idiopathic gastroparesis compared to diabetic gastroparesis (40% vs 20%, respectively).

Diagnosing gastroparesis

There are three diagnostic tests objectively demonstrating delayed gastric emptying: scintigraphy, wireless motility capsule, and breath testing . The most commonly used test is solid-phase scintigraphy , in which a ^99m Tc sulfur colloid-marked egg sandwich is ingested by the patient along with a piece of toast and jelly. Thereafter, the percent of food remaining in the stomach is reported at key time points: 1 h (37–90%), 2 h (30–60%), and 4 h (0–10%). The most reliable parameter is gastric retention at 4 hours, although measurement at 1 and 2 hours is also important, since prolongation of early phases may be associated with symptoms of gastroparesis . The above-mentioned diagnostic methods can help establish a diagnosis, but they provide no insight into the pathophysiology of the disease, the underlying cause (idiopathic, diabetic, or infiltrative process) or individual therapy.

In order to find answers to these questions, full-thickness gastric biopsies have been viewed as a promising modality. It provides information on ganglia abnormality, reduction in ICC count and inflammatory processes, all of which can be potential markers for grading the disease, predicting response to treatment and prognosis. Examination of deep gastric tissue may lead to a better understanding of pathophysiology of the disorder and bring the prospect of new therapeutic options.