Understanding the Pathogenesis of Slow-Transit Constipation: One Step Forward

Abstract

Chronic constipation is a common clinical complaint, particularly in persons aged C65 or\15 years. According to the national ambulatory medical care survey data collected in 2004, it is the second most common ambulatory care diagnosis after gastroesophageal reflux disease in the United States, with 5.4 million prescriptions filled in addition to a very large number of nonprescription medications purchased by constipated patients [1]. Medical management of constipation may include the intake of bulking or wetting agents, or osmotic or stimulant laxatives, or undergoing behavioral modification, biofeedback therapy, sacral nerve stimulation, or even colonic pacing. Patients refractory to medical treatment may eventually require surgical interventions with partial or total colectomy [2]. A variety of structural, mechanical, metabolic, or functional causes can lead to chronic constipation [3], including slow-transit constipation. Slow-transit constipation is a motility disorder characterized by markedly increased total bowel transit time when measured with radioactive markers, normal radiologically assessed bowel diameter, and no evidence of megacolon or aganglionosis. Since there are no diagnostic histologic features that can help determine its underlying etiology, the condition is frustrating not only to patients, gastroenterologists, and colorectal surgeons, but also to pathologists. Even with colectomy specimens, histologic examination can be completely normal or show only secondary nonspecific changes as a result of chronic constipation or its treatment effects [4]. Common abnormalities may include melanosis coli, cryptitis, crypt abscess, mucosal prolapse, and pneumatosis coli. Typically, no appreciable morphologic abnormalities are observed in the nerve plexuses, ganglion cells, and muscle fibers. The pathogenesis of slow-transit constipation remains largely unknown. Earlier investigations have focused on quantitative alternations of the interstitial cells of Cajal (ICC), the pacemaker of the gastrointestinal tract. Using antibodies against c-kit (CD117) or DOG1 (discovered on GIST-1, also known as Ano1 and TMEM16A), a complete absence or significant reduction in the number of ICC in colon specimens resected from patients with slow-transit constipation in comparison with normal controls was reported [5, 6]. Wang et al. [7] even suggested a value of 7 ICCs/high power field in the inner circular muscle layer as a threshold value in order to confirm the diagnosis of slowtransit constipation. Yet, this measurement is difficult for pathologists to report due to the technical challenges of counting ICC density in clinical specimens, unless the cells are completely absent. The normal ICC count may also vary depending on detecting methods and the age of patients [8]. Furthermore, one study reported no relationship between ICC numbers and slow-transit constipation [9]. Only one study described decreased expression of c-kit mRNA and protein in colon specimens from patients with slow-transit constipation in comparison with controls [10]. However, c-kit gene mutations appear to be an infrequent event in this group of patients: in a study of 23 patients, only one case showed a missense mutation, although two polymorphism sites in the intron region were also detected, which may affect exon–intron splicing [11]. Many other pathophysiological abnormalities in the diseased colon may be associated with slow-transit & Hanlin L. Wang hanlinwang@mednet.ucla.edu