Atsuyuki Yamataka

A lack of intestinal pacemaker (c-kit) in aganglionic bowel of patients with Hirschsprung's disease.

Recent experimental studies in mice have shown that the proto-oncogene c-kit plays a key role in the development of a component of the pacemaker system that is required for generation of autonomic gut motility. These studies further suggest that interaction of the c-kit receptor and its ligand (stem cell factor, SCF) is critical for the development of the enteric nervous system. The authors investigated the presence of c-kit-positive (c-kit+) cells as well as the expression of SCF in bowel from 12 patients with Hirschsprungs disease (HD), 4 patients with total colonic aganglionosis (TCA), 2 patients with extensive aganglionosis (EA) and 14 controls. Our methods involved the use of immunohistochemistry with antihuman c-kit sera and antihuman SCF sera. A few c-kit+ cells were found in the muscle layers of aganglionic bowels from HD, TCA and EA, in contrast to many c-kit+ cells in ganglionic bowel segments from control, HD, and TCA patients. Expression of SCF was identified in the muscle layers as well as in myenteric plexus of ganglionic bowel, in contrast to its absence in the muscle layers of aganglionic bowel specimens. A lack of c-kit and SCF might be of significance for autonomic gut dysmotility in aganglionic bowel segments of patients with HD and allied disorders such as chronic idiopathic intestinal pseudo-obstruction.

Complications after cyst excision with hepaticoenterostomy for choledochal cysts and their surgical management in children versus adults

The aim of this study was to review the cases 200 children and 40 adults who had cyst excision combined with hepaticoenterostomy (CEHE) for choledochal cyst, with particular emphasis on post-CEHE complications and their surgical management. Patients who had CEHE at the age of 15 years or less were defined as children, and those aged 16 years or older were defined as adults. The mean age when patients became initially symptomatic was 3 years in children and 26 years in adults. Eleven adults became symptomatic as children (< or = 15 years of age). The mean age of CEHE in children and adults was 4.2 years and 35 years, respectively. The time interval between the onset of initial symptoms and CEHE was significantly less in children than in adults (P < .0001). Of the 200 children, 176 had primary CEHE, and 24 had secondary CEHE converted from cystoenterostomy or other biliary surgery. Seventy children had intraoperative cyst endoscopy, which enabled us to examine the proximal intrahepatic bile ducts for stenosis and debris, and to wash out debris, protein plugs, and stones from the intrapancreatic ducts. Of the 40 adults, 22 had primary CEHE, 18 had secondary CEHE. The mean follow-up period was 10.9 years in children and 10.7 years in adults. The number of patients with post-CEHE complications in children and adults was 18 (9.0%) and 17 (42.5%), respectively. The post-CEHE complication rate in children was significantly lower than in adults (P < .0001). The 18 children had 25 post-CEHE complications such as cholangitis, intrahepatic bile duct stones, pancreatitis, stone formation in the intrapancreatic terminal choledochus or pancreatic duct, and bowel obstruction. Twenty-seven post-CEHE complications developed in the 17 adults including 2 cases of cholangiocarcinoma. There were no post-CEHE complications in the 70 children who had intraoperative cyst endoscopy. No stone formation was seen in the 145 children who had CEHE at the age of 5 years or less. Eight stone formations were seen in seven (12.7%) of the remaining 55 children aged over 5 years. Stones developed in seven (17.5%) adults. The incidence of post-CEHE stone formation in children aged 5 years or less was significantly lower than in other children and adults (P < .0001). Reoperation was required in 15 children: revision of hepaticoenterostomy in 4, percutaneous transhepatic cholangioscopic lithotomy (PTCSL) in 1, excision of intrapancreatic terminal choledochus in 2, endoscopic sphincterotomy of the papilla of Vater in 1, pancreaticojejunostomy in 1, and laparotomy for bowel obstruction in 6. Ten adults required reoperations: revision of hepaticoenterostomy in 2, PTCSL in 2, left hepatic lobectomy in 1, endoscopic sphincterotomy in 2, exploratory laparotomy in 2, and adhesiolysis in 1. The authors conclude that early diagnosis followed by CEHE is the treatment of choice for choledochal cyst, and intraoperative cyst endoscopy is recommended as a valuable adjunct to CEHE.

Abnormal distribution of intestinal pacemaker (C-KIT-positive) cells in an infant with chronic idiopathic intestinal pseudoobstruction

BACKGROUND Chronic idiopathic intestinal pseudoobstruction (CIIPO) is a rare syndrome with an obscure pathogenesis. The proto-oncogene c-kit encodes a transmembrane tyrosine kinase receptor C-KIT that is critical for the development of the interstitial cells of Cajal, cells that are regarded as being the pacemaker cells of the gut. Thus, C-KIT immunopositive (C-KIT-) cells in the muscle layers of the bowel are considered to be intestinal pacemaker cells. METHODS In this study, the distribution of intestinal pacemaker cells was examined for the first time using C-KIT immunohistochemistry in an infant with CIIPO. RESULTS C-KIT+ cells were found lying on either side of the border between the two muscle layers (longitudinal and circular) of the bowel and dispersed unevenly throughout both muscle layers. Myenteric plexuses were not demarcated by C-KIT+ cells. In contrast, in controls, C-KIT+ cells were located distinctly between the two muscle layers of the small bowel and dispersed evenly throughout the muscle layers of the colon. Myenteric plexuses were clearly demarcated by C-KIT+ cells. CONCLUSIONS This case demonstrates for the first time that there is abnormal distribution of intestinal pacemaker cells in CIIPO and provides new evidence that abnormal c-kit gene expression may be responsible for autonomic gut dysmotility. C-KIT immunohistochemistry may be an indispensable tool for diagnosing CIIPO.

Long-term postsurgical outcome of biliary atresia

BACKGROUND/PURPOSE A successful Kasai procedure is effective in creating biliary drainage and radically altering the natural history of infants with biliary atresia (BA). Since its introduction in the 1950s, long-term follow-up would appear to show that only 30% to 50% of patients have a good long-term prognosis despite initially good surgical outcome. The authors reviewed their experience in treating BA from 1968 to 1997 to assess long-term outcome. MATERIALS AND METHODS The records of 163 patients treated surgically for BA from 1968 to 1997 were reviewed. Forty-eight (29%) were alive at the end of 1997, of whom, 14 had received liver transplants (LT). Surviving patients who had not undergone transplantation were divided into two groups according to clinical condition: group A, normal liver function without cholangitis (CG) and portal hypertension (PH) and group B, liver dysfunction with CG or PH. The study period was divided arbitrarily into three periods, 1968 to 1975 (period I, n = 34); 1976 to 1985 (period II, n = 81); 1986 to 1997 (period III, n = 48). RESULTS Thirty-four patients were alive without LT at the end of 1997. There were eight patients (mean age, 16.3+/-4.8 years) in group A, and 26 patients (mean age, 14.3+/-7.6 years) in group B. Recently, four group A patients (mean age, 19.3+/-1.9 years) shifted to group B because of sudden deterioration in condition involving severe CG with multiple bile lakes (n = 2), uncontrollable intestinal bleeding (n = 1), and liver atrophy (n = 1). Survival deteriorated with length of follow-up. There were three survivors from 34 patients treated in period I, 16 survivors from 81 patients treated in period II (three had LT), and 29 survivors from 48 patients treated in period III (11 had LT). CONCLUSIONS Although satisfactory bile drainage can be obtained with portoenterostomy, our data suggest that liver function can deteriorate progressively, with a possible turning point in late adolescence, indicating that as the length of follow-up increases, clinical assessment should be regular and comprehensive. The timing of LT in postoperative BA patients with deteriorating liver function is a vital management issue.

Lack of intestinal pacemaker (C-KIT-positive) cells in infantile hypertrophic pyloric stenosis☆

The pathogenesis of infantile hypertrophic pyloric stenosis (IHPS) is not well understood. Recent studies have shown that the protonocogene c-kit is essential for the development or maintenance of autonomic gut motility, and also show that the c-kit gene protein product (C-KIT) positive cells in the mammalian gut are responsible for intestinal pacemaker activity. This study examines cells in the pyloric muscles of 23 patients (16 with IHPS, 7 controls) for the presence of the C-KIT (C-KIT+), using immunohistochemical techniques with antihuman C-KIT sera. In the controls, many C-KIT immunoreactive (IR+) cells were observed in the muscle layers. The myenteric plexuses were demarcated by a moderate number of C-KIT-IR+ cells. However, in the IHPS patients, C-KIT-IR were either absent or significantly reduced. No C-KIT-IR+ cells were found around the myenteric plexuses. These findings suggest that a lack of c-kit expression (as an indicator of intestinal pacemaker activity) in the hypertrophic pyloric smooth muscles may be an important factor in the pathogenesis of IHPS.

Choledochal cysts: Special emphasis on the usefulness of intraoperative endoscopy

Long-term complications after excisional surgery for choledochal cyst include stone formation within the intrahepatic bile duct (IHBD) and within the intrapancreatic portion of the bile duct (IPBD). The authors reviewed 180 patients with choledochal cysts (137 women) seen during a 30-year period and report their recent experience with intraoperative cyst endoscopy. Primary cyst excision with hepaticoenterostomy was performed in 150 cases, and a secondary cyst excision, after various lesser drainage procedures, in 24. Six children were treated early in the series with a cyst enterostomy. The mean age and follow-up period were 4.3 and 9.4 years, respectively. At surgery, dilatation of the IHBD was identified in 96 patients, and protein plugs or stones were observed in 31 common pancreaticobiliary channels. Fifty-five common channels were noted to be dilated. Hepaticojejunostomy was performed in 123 patients without intraoperative endoscopy. Late stone formation occurred within the IHBD in 4 of these cases and within residual segments of intrapancreatic cyst in 2 (mean age and follow-up period were 4.9 and 13.0 years, respectively). Intraoperative endoscopy was performed in 51 patients (mean age and follow-up period 3.6 and 4.3 years), and stone formation has not been observed in any patients in this group. Intraoperative cyst endoscopy is recommended as a valuable adjunct to choledochal cyst excision.

Pyloromyotomy Versus Atropine Sulfate for Infantile Hypertrophic Pyloric Stenosis

PURPOSE Atropine sulfate (atropine) and pyloromyotomy were compared for managing infantile hypertrophic pyloric stenosis (IHPS). METHODS From 1996 to 1998, cases of IHPS treated surgically (pyloromyotomy; n = 20) or medically (atropine; n = 14) at separate institutions were compared retrospectively with regard to status on presentation, physical symptoms and signs, progress, and costs. Atropine was given orally, then intravenously if ineffective. Refractory cases were referred for pyloromyotomy. RESULTS All subjects were matched for clinical and physiological status on admission. Oral atropine alone was effective in 11 cases, was converted to intravenous atropine in 2 cases, and was terminated in 1 case because of hematemesis. Two cases were referred for pyloromyotomy. All pyloromyotomies were successful. Atropine took on average, 2.6 days to take effect. The difference in time taken for normalization of pyloric muscle thickness between the 2 groups was not significant. Average time to return to full feeding was longer in the atropine group (P<.01). Costs were lower in the atropine group (P<.01). There were 2 wound infections in the pyloromyotomy group, but no adverse effects of atropine. There were no recurrences in either group. CONCLUSION This study provides reasonable evidence to support a trial of atropine in IHPS.

Intestinal pacemaker C-KIT+ cells and synapses in allied Hirschsprung's disorders.

The cause of bowel dysmotility in allied Hirschsprungs disorders (AHDs) such as hypoganglionosis (HYPG), immature ganglia (IMG) and neuronal intestinal dysplasia (NID) remains unexplained. Recent experimental studies in mice have shown that c-kit gene product positive (C-KIT+) cells are responsible for intestinal pacemaker activity and that c-kit is also closely involved in synapse formation. To further understand the pathophysiology of AHDs, the authors used immunohistochemistry to study the distribution of C-KIT+ cells and synapses in the muscle layers of normal bowel from controls (12 cases) and bowel from patients with AHDs (10 patients; mean age, 3.0 years; 5 HYPG, 3 NID, 2 IMG). Anti-human C-KIT serum and monoclonal antibody 171B5 (a novel marker of synapses) were used for visualization of C-KIT+ cells and 171B5+ synapses, respectively. In normal bowel from controls and patients with AHDs, moderate to many C-KIT immunoreactive (C-KIT-IR+) cells were observed in the muscle layers. Myenteric plexuses were clearly demarcated by C-KIT-IR+ cells. 171B5 immunoreactive (171B5-IR+) synapses were abundant in the muscle layers and within the myenteric plexuses. In contrast, the number of C-KIT-IR+ cells or 171 B5-IR+ synapses was reduced in the muscle layers of bowel affected by AHDs, except within the myenteric plexuses, where there was a moderate to large number of 171B5-IR+ synapses identified. A lack of intestinal pacemaker C-KIT+ cells may be of great significance with respect to the bowel dysmotility associated with AHDs and also to the abnormal synapse formation seen in the muscle layers of bowel affected by these disorders.

Initial experience with non-breath-hold magnetic resonance cholangiopancreatography: A new noninvasive technique for the diagnosis of choledochal cyst in children

BACKGROUND/PURPOSE Magnetic resonance cholangiopancreatography (MRCP) is an emerging tool for the noninvasive evaluation of the pancreaticobiliary tree. METHODS Non-breath-hold MRCP was used in three children to evaluate choledochal cyst; a first for this new modality of diagnostic imaging. In all cases, the intrahepatic and extrahepatic bile ducts, and the pancreatic duct were clearly visualized. RESULTS Two cases were found to have a fusiform choledochal cyst, and non-breath-hold MRCP demonstrated pancreaticobiliary malunion and a long common channel. In the remaining case, the size and location of the huge cyst prevented visualization of any pancreaticobiliary malunion. Endoscopic retrograde cholangiopancreatography (ERCP) in this patient failed to provide any additional information. All patients underwent cyst excision with hepaticoenterostomy, and made an uneventful recovery. CONCLUSIONS Our initial experience suggests that non-breath-hold MRCP is a reliable method for the diagnosis of choledochal cyst in children and could replace ERCP.

Abnormal distribution of nerve terminals in infantile hypertrophic pyloric stenosis

Smooth muscle biopsy specimens obtained from nine infants with infantile hypertrophic pyloric stenosis (IHPS) and from three controls were studied immunohistochemically with respect to the distribution of nerve terminals and neurofilaments. To label nerve terminals and neurofilaments, monoclonal antibodies (MAb) 171B5 and 2F11 were used, respectively. In all specimens of the control group, nerve terminals were numerous in both the myenteric plexus and the muscle layer. There were abundant neurofilaments in the myenteric plexus and a moderate number in the muscle layer. In all specimens of the IHPS group, the density of nerve terminals and neurofilaments was reduced in the muscle layer. In the myenteric plexus, there was no such reduction. The results indicate poor neuronal innervation of the muscle layer in the pylorus of infants with IHPS. This poor innervation may be related to the pathogenesis of pyloric stenosis and hypertrophy.