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Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, double-blind, dose-ranging study comparing placebo with omeprazole, 20 or 40 mg given once daily in the morning. Esophagitis grade 2 was present in 44% of patients, grade 3 in 37% of patients, and grade 4 in 19% of patients. Endpoints, defined as complete relief of heartburn and complete esophageal mucosal healing, were assessed after 4 and 8 weeks of treatment. Both omeprazole doses were significantly superior to placebo in complete endoscopic healing. After 8 weeks of treatment, 73.5% of patients in the 20-mg omeprazole group and 74.7% in the 40-mg omeprazole group, compared with 14.0% in the placebo group, had complete healing of the esophageal mucosa. At the end of the study, complete relief of daytime heartburn was obtained in 79.5% of patients in the 20-mg omeprazole group, 81.6% in the 40-mg omeprazole group, and 37.2% in the placebo group (P less than or equal to 0.05). Complete relief of nighttime heartburn was noted by 79.5% of patients in the 20-mg omeprazole group, 85.1% in the 40-mg omeprazole group, and 34.9% in the placebo group (P less than or equal to 0.05). The median time to complete relief of daytime and nighttime heartburn occurred earlier in the 40-mg group than in the 20-mg group (9 vs. 17 days and 9 vs. 20 days, respectively); however, these differences were not statistically significant. Relief of acid regurgitation and dysphagia also occurred earlier in the 40-mg group. Omeprazole was well tolerated in this group of patients. No unexpected adverse experiences occurred. The results of this study confirm those of six multicenter, international trials in which omeprazole in doses of 20-60 mg provided a degree of esophageal mucosal healing and complete relief of reflux symptoms superior to any other medical treatment.

A 50-year-old woman with acute onset of right lower quadrant pain and hematochezia proved to have segmental ischemic colitis associated with methamphetamine abuse. The diagnosis was established by colonoscopy with biopsy, and abdominal angiography revealed no thrombosis, vasculitis, or vasospasm. The condition resolved within 10 days. Since methamphetamine abuse is increasing, physicians should be aware of its potential to produce intestinal ischemia.

SUMMARY Methods: this US multicentre, randomized, double-blind, placebo-controlled, parallel group study determined the effects of two twice daily oral famotidine regimens on symptom relief and healing of erosive oesophagitis in patients with gastro-oesophageal reflux disease. Three hundred and eighteen patients were enrolled: 66 received placebo, 125 received famotidine 20 mg b.d., and 127 received famotidine 40 mg b.d. Patients maintained diaries of their symptoms. Endoscopy was performed at weeks 0 and 6, and again at week 12 if healing had not occurred. Results: healing at 6 and 12 weeks was (respectively) 48% (P < 0.01 vs. placebo) and 69% (P≫ 0.01 vs.placebo) for famotidine 40 mg b.d.; 32% and 54% (P≫ 0.01 vs. placebo) for famotidine 20 mg b.d., and 18% and 29% for placebo. At both 6 and 12 weeks the healing rates of famotidine 40 mg b.d. were significantly greater than placebo and famotidine 20 mg b.d. Compared to placebo, famotidine produced more frequent global symptom improvement and more rapid heartburn relief. There were no significant differences among treatment groups in the incidence of clinical or laboratory adverse events. Conclusions: famotidine 40 mg b.d. was a better regimen than famotidine 20 mg b.d. or placebo. The clinical efficacy paralleled the previously documented effect of the famotidine regimens on decrease of oesophageal acid exposure.

Background: Antireflux therapy has generally failed to induce regression of Barrett's epithelium. It was hypothesized that squamous epithelium could be restored if the columnar tissue was ablated while gastric acid secretion was suppressed. Methods: Ten white men with Barrett's esophagus received 40 mg of omeprazole daily. Thereafter, every 2–5 weeks they underwent videotaped endoscopies to argon laser photoablate columnar tissue, obtain biopsy specimens, and assess results. Squamous re-epithelialization was assessed by correlation of videotapes and directed biopsies. Results: Patients had one to eight areas ablated, totaling 0.5–12.0 cm 2 . Videotape assessments were corroborated by biopsy in all but one instance. Thirty-eight of 40 treatment locations partially or completely re-epithelialized with squamous tissue. Squamous regrowth appeared to occur by spread from contiguous squamous borders and de novo from glandular tissue. Regrowth was influenced by the extent of squamous borders and completeness of ablations. Nonablated glandular tissue persisted beneath squamous epithelium. Conclusions: Ablation of Barrett's epithelium and suppression of acid secretion facilitated squamous re-epithelialization. A progenitor cell within the metaplastic tissue has the potential to differentiate normally.

The effect of bile acids on the formation of biliary thrombi in protoporphyrin-induced cholestasis was determined by perfusing isolated rat livers with taurocholate, chenodeoxycholate and ursodeoxycholate with and without protoporphyrin. Protoporphyrin-induced reduction of bile flow was similar in the presence of each bile acid. The cholestasis was greater at high doses (2,000 to 10,885 nmol) than at low doses (1,500 nmol) of protoporphyrin, unrelated to the amount of lactate dehydrogenase released into the perfusate, and it was not altered by increasing bile acid infusions. Bile acid excretion was inhibited by high protoporphyrin doses. Periportal birefringent pigment deposits were seen in canaliculi and ductules when the biliary protoporphyrin concentration exceeded 161 nmol/ml, 345 nmol/ml and 1,036 nmol/ml for ursodeoxycholate, chenodeoxycholate and taurocholate, respectively; or, when the protoporphyrin (nanomole) to bile acid (micromole) ratio exceeded 3.23, 7.03 and 23.43, respectively. The maximal ratio of ductular deposits to portal tract deposits examined was 0.9. Electron microscopy showed these deposits were associated with canalicular thrombi. Thus, biliary thrombi were produced by infusion of bile acids and protoporphyrin. The occurrence of thrombi varied with bile acid structure. Explanations for this finding are speculative. The presence of periportal thrombi, however, did not influence the degree of functional cholestasis.(HEPATOLOGY 1990; 11:757-763.)

The case of a woman with intermittent upper gastrointestinal hemorrhage beginning 1 month after cholecystectomy is presented. Celiac arteriography demonstrated an intrahepatic arterial aneurysm, and laparotomy confirmed the presence of hemobilia. Ligation of the common hepatic artery was performed, and bleeding has not recurred.

The pathogenesis of liver disease in protoporphyria has been presumed to result from the hepatic deposition of protoporphyrin. To examine the effects of protoporphyrin on hepatic bile flow and histopathology, studies were performed employing an isolated, in situ, rat liver perfusion system. Rat livers in the control group were perfused with 0-80 μmol sodium taurocholate/h. Rat livers in the experimental group were perfused with sodium taurocholate and (a) sufficient quantities of protoporphyrin to produce maximal canalicular secretion and (b) perfusate protoporphyrin concentrations of 0.01, 0.1, and 1 μM. The administration of protoporphyrin sufficient to achieve maximal canalicular secretion was found to significantly reduce bile flow in rats infused with 0, 40, and 80 μmol sodium taurocholate/h. Linear regression analysis defined the relationship between bile flow and biliary bile acid secretion and showed that the bile acid-independent fraction of bile flow was reduced (P < 0.01). Bile acid-dependent flow was unaffected and there was no significant difference in biliary bile acid secretion rates between control and protoporphyrin-perfused livers. Perfusion of rat livers with varying concentrations of protoporphyrin demonstrated the reduction of bile flow was dose-related. Analysis of perfusate enzyme activity did not reveal abnormalities that could account for the cholestasis. Studies to evaluate the effect of protoporphyrin on regional hepatic hemodynamics were inconclusive. Histopathological studies of control and protoporphyrin-perfused rat livers did not show abnormalities on light microscopy. However, canalicular dilatation, distortion, and loss of microvilli were present in the protoporphyrin-perfused livers examined by transmission electron microscopy. Although ultraviolet microscopy showed diffuse fluorescence of the hepatocytes and canaliculi of protoporphyrin-perfused livers, the deposition of protoporphyrin in amorphous or crystalline forms was notably absent in studies with polarizing and transmission electron microscopy. These studies provide evidence that protoporphyrin has hepatotoxic properties that affect the canalicular secretory apparatus. The mechanism(s) responsible for the injury require further clarification.

Determination of the efficacy and safety of endoscopic laser photocoagulation to control upper gastrointestinal bleeding is prerequisite to the general application of this treatment in humans. We studied photocoagulation hemostasis, penetration, and perforation produced by a 55-W neodymium-yag (Nd:YAG) laser to control standardized experimental gastric bleeding lesions in a heparinized canine model. Photocoagulation of bleeding lesions was 100% successful with an application time of 3.56 +/- 1.65 sec (mean +/- SD). Histologic examintion of the gastric wall revealed a depth of injury to the muscularis externa of 40-100% with greater than 2 sec photocoagulation. Continuous photocoagulation exceeding 4 sec produced an 80-100% depth of muscle injury. Perforation of the gastric wall occurred after 9.6 +/- 1.5 sec, and all dogs studied after perforation survived. These studies indicate that Nd:YAG photocoagulation is an effective method to control experimental gastric bleeding lesions with a ratio between mean photocoagulation hemostasis and perforation times of approximatley 1:3. Further studies are required to define the implications of photocoagulation injury to muscle and the role of the gastric serosa in laser applications.

This report describes two patients with esophageal columnar epithelium (Barrett's esophagus) in which microinvasive adenocarcinoma developed. Case 1 had multiple foci of carcinoma in situ contiguous with epithelium resembling gastric and intestinal mucosa. Case 2 had signet-ring type adenocarcinoma. Surveillance for malignant transformation in columnar esophageal epithelium should be routinely performed, and because of its focal nature, multiple biopsies and cytologic examination should be carried out. The presence of carcinoma in situ should lead to consideration of excision of the affected esophagus.

In order to correlate histopathology and cell turnover in esophageal tissue in patients with esophageal columnar epithelium, biopsy specimens from 11 patients were studied. Two of the patients had adenocarcinoma of the esophagus not present in the specimens studied. In the heterogeneous esophageal columnar epithelium, the DNA synthesis phase averaged 10.4 ± 0.3 hr; labeling index of cells in the crypt-like structures was 23.3 ± 0.3%; generation time was 44.6 ± 1.2 hr, and the mitotic index was 1.82 ± 0.07%. Significant differences were not present among specimens with columnar epithelium but they differed from cell proliferation in adjacent squamous epithelium where S phase was similar but labeling and mitotic indexes were lower and generation time increased to 105 ± 6 hr. In the 2 patients with adenocarcinoma of the esophagus, and in 1 of 9 without adenocarcinoma, labeling of surface columnar cells after brief exposure to [3H]thymidine was present and suggests that this may be a manifestation of early malignant change.

At 12 weeks of age, the patient whom we report underwent cholangioduodenostomy for treatment of complete atresia of the common bile duct. After surgery, her course was punctuated by episodes of cholangitis and jaundice. When she was 25 years of age, a liver biopsy showed biliary cirrhosis. Percutaneous cholangiography revealed dilated and deformed intrahepatic biliary ducts containing stones. Surgical removal of the stones and revision of the cholangioduodenal anastomosis was performed. Intrahepatic cholelithiasis has not previously been reported as a complication of this disorder. Her survival is the longest reported in the world literature for this condition, and emphasizes the need to vigorously pursue potentially operable cases.

Upper gastrointestinal polyps have been considered an uncommon finding in patients with Gardner's syndrome and familial polyposis coli. Investigators from Japan, however, have recently reported finding gastric and duodenal polyps in a high percentage of Japanese patients with these conditions. We endoscopically examined 11 affected members of the originally described Gardner's syndrome kindred to determine if upper gastrointestinal polyps also occurred in patients with Gardner's syndrome living in the United States. Six of the patients were found to have numerous small polyps of the gastric fundus and body. Polyp histology in 5 of the 6 patients was consistent with fundic gland hyperplasia. Biopsy specimens from the remaining patient demonstrated normal mucosa only. Another patient with no fundic polyps had a single antral polyp that was an adenoma. Eight patients exhibited small polyps of the duodenum. Biopsy specimens were obtained in 7 of the 8. All polyps biopsied were adenomas. The terminal ileum was examined by endoscopy in 9 of the 11 study patients. All 9 had ileal polyps, but the polyps were adenomas in 6 patients and lymphoid aggregates in 3 patients. The results indicate that upper gastrointestinal polyps are a common pleiotropic manifestation of the genetic defect responsible for Gardner's syndrome.

Two patients with massive gastrointestinal bleeding are reported. One bled from an aneurysm of a branch of the left hepatic artery, the blood reaching the bowel through communication with the biliary tree. The second had an aneurysm of a branch of the splenic artery which communicated with the pancreatic duct. This type of bleeding is intermittent and, consequently, actual extravasation of contrast media is not always seen. Therefore, if one sees an aneurysm of a visceral artery, even if it does not directly supply the enteric tract, one should consider the possibility that it is the origin of the hemorrhage. Pathogenesis, diagnostic modalities, and therapeutic implications are discussed.

Serial morphological, secretory, and serological observations of a patient with Menetrier's disease disclosed hypergastrinemia, antibodies to parietal cells and dietary substances, and an acute reduction of gastrointestinal protein loss after atropine administration. Transformation of the gastric mucosa from hypertrophy to atrophic gastritis was associated with disappearance of the protein-losing gastroenteropathy and serum antibodies and reduction of the serum gastrin concentration.

A patient with cirrhosis developed hemoperitoneum, lactic acidosis, and hyperphosphatemia in the absence of shock. At post-mortem examination occult multicentric hepatocellular carcinoma eroding the liver capsule was present. The case emphasizes the central role of the liver in lactic acidosis, indicates that hemoperitoneum may precipitate this complication, and documents the association of lactic acidosis and hyperphosphatemia.

Twenty-eight patients with chronic, incapacitating upper abdominal pain after cholecystectomy had excision of the common wall between the terminal bile duct and duct of Wirsung (ampullary septum). Twenty-two also had a sphincteroplasty: six had had this procedure previously. Pancreatic function studies, scintiscans, ultrasound and pancreatograms were non-diagnositic. Hyperamylasemia was an uncommon finding. Eight patients were found to have evidence of mild pancreatitis at exploration. There was gross scarring of the ampullary septum in 22 cases. Histologic examination revealed inflammation in 12 septa; the degree of fibrosis could not be assessed since 14 control septa from autopsy material free from biliary tract disease revealed a comparable degree of collagen and smooth muscle. There were no deaths, and minimal morbidity. In follow-up from seven to 59 months (mean = 26), 16 patients are relatively free of pain, five have occasional episodes which require non-narcotic analgesics, and seven have gained no relief from the operative procedure. A randomized controlled trial is recommended.

Pancreatography is a valuable diagnostic technic to identify structural changes in the pancreatic ductal system. Although specific diagnoses based on ductal changes are not always possible, patients with surgically normal glands and those showing changes of chronic pancreatitis were reliably identified in this series. Patients evaluated for postcholecystectomy pain usually had normal pancreatograms and grossly normal pancreatic glands at the time of surgical exploration. The overall consistency in interpretation of pancreatograms by experienced radiologists was approximately 80 per cent. Pancreatic cancer was poorly predicted due to either minimal changes in the ductal system or inability to distinguish gross changes from those seen with chronic pancreatitis.

Examination of gallbladder bile in the sediment of duodenal drainage obtained after magnesium sulfate stimulation was used to evaluate the presence or absence of gallbladder disease in thirty-four patients with symptoms suggestive of cholecystitis and normal or equivocal oral cholecystography. Ten patients had positive tests and nine of these had cholecystectomy. All nine had pathologically confirmed cholecystitis and seven of nine had cholelithiasis. Three patients with negative test results had laparotomy and normal gallbladders. The remaining twenty-one patients with negative tests have been followed up to three years, and none have returned with evidence of biliary tract disease. The results of this study suggest that duodenal drainage (Meltzer-Lyon test) is a valuable adjunctive diagnostic study in patients with gallbladder disease symptoms in whom normal or equivocal oral cholecystograms are obtained.

Asymptomatic bile leakage developed in a woman following percutaneous liver biopsy. The case is remarkable because features of cholestasis were not present at the time of biopsy, the bile leak occurred through the needle tract in the liver, bilious ascites occurred without signs of acute peritonitis, and the complication was the initial manifestation of extrahepatic biliary obstruction due to encasement of the common bile duct by histiocytic lymphoma. (Arch Intern Med139:245-246, 1979)