A comparison of low-dose maintenance treatment with enprostil against ranitidine in the prevention of duodenal ulcer recurrence.

Enprostil, a prostaglandin E2 analogue, is effective in healing acute duodenal ulcer but its value in preventing recurrence, when given daily for maintenance therapy, is uncertain. In this three-centre study we compared enprostil and ranitidine maintenance therapy; the latter is known to reduce duodenal ulcer relapse rates. Patients whose duodenal ulcers had been healed by treatment with an H2-receptor antagonist were randomized to receive single-blind treatment with either 35 micrograms enprostil (n = 64) or 150 mg ranitidine (n = 64) at bedtime for periods of up to 1 year. Endoscopy was routinely performed at 3 months at one centre, and at 6 and 12 months at all three centres, or whenever ulcer symptoms recurred. Clinical assessment and laboratory investigations were performed every 3 months. Relapse, defined as recurrent ulcer with or without pain, or erosions with pain, was significantly greater in patients on enprostil, the comparative rates at 3, 6 and 12 months were: enprostil 23, 31 and 36% ranitidine 6, 12 and 17% (P = 0.013; P = 0.03 and P = 0.03, respectively). Thirty-one patients reported adverse events, the most common being headache (enprostil = 6, ranitidine = 2) and mild diarrhoea (enprostil = 6, ranitidine = 0). Four patients on enprostil were withdrawn for adverse events, although none terminated because of diarrhoea. There were no clinically significant changes in haematology or biochemistry. Enprostil may reduce duodenal ulcer relapse but at a dose of 35 micrograms nightly, it is less effective than 150 mg ranitidine nightly.

Improved survival following injection sclerotherapy for esophageal varices: final analysis of a controlled trial.

Long-term follow-up (median: 37 months; range: 19 to 68) of the 116 patients (56 sclerotherapy, 60 control group) entered into a controlled trial of endoscopic variceal sclerotherapy has shown a total of 18 deaths in the sclerotherapy group, including five from variceal bleeding compared with 32 deaths in the control group (p less than 0.01), of which 25 were from variceal hemorrhage (p less than 0.001). Survival as assessed by cumulative life analysis was significantly better in those treated by sclerotherapy (p less than 0.001). Both the cumulative proportion of patients rebleeding and the total number of episodes of variceal hemorrhage were also significantly less in the sclerotherapy group (p less than 0.01). Recurrence of varices was observed in 27 of 45 patients in whom variceal obliteration was initially observed at a median of 11 months (range: 2 to 27) later, although in only 12 of these did bleeding recur and was the cause of death in one.

B1 selective adrenoreceptor blockade for the long term management of variceal bleeding. A prospective randomised trial to compare oral metoprolol with injection sclerotherapy in cirrhosis.

Oral metoprolol, in a dose sufficient to reduce resting pulse rate by 25%, was compared with repeated injection sclerotherapy for the long term management of variceal bleeding. The prospective, randomised study was undertaken in 32 patients with biopsy proven cirrhosis and variceal bleeding who were Grade A or B on a modified Child's classification. In the 15 patients receiving metoprolol, portal pressure showed a mean fall of 3.7 mmHg (17.3 +/- 1.2 to 13.6 +/- 1.2 mmHg, p less than 0.01) after four weeks of continuous therapy, as compared with pretreatment levels. Nine of the 15 patients taking metoprolol had further bleeding (total of 21 episodes) compared with six of 17 in the sclerotherapy group (nine episodes). The risk of bleeding per patient/month of follow up was three times higher in the metoprolol group compared with those treated by sclerotherapy (0.14 and 0.04 respectively, p less than 0.025). Rebleeding in the metoprolol group occurred in six of the patients who had a fall in portal pressure of 10% or more.

Injection sclerotherapy for oesophageal varices: a prospective randomised trial of different treatment schedules.

A prospective randomised study to compare the efficacy and complications of injection sclerotherapy carried out at intervals of one week and three weeks up to the time obliteration of varices was achieved, was undertaken in 55 patients (48 cirrhosis, six portal vein thrombosis, one nodular regenerative hyperplasia). The number of courses of injection required for obliteration of the varices was not different in the two groups and despite a shorter time scale for obliteration in the weekly treated patients the frequency with which further episodes of bleeding occurred before that was not significantly less. Mucosal ulceration during the period required for obliteration was observed at endoscopy more frequently in the weekly treated patients but was not associated with a greater frequency of postinjection pain, dysphagia or of long term stricture formation.

A prospective randomized study of two sclerotherapy techniques for esophageal varices.

In a study designed to compare the efficacy and safety of two techniques of injection sclerotherapy, 40 patients (30 with cirrhosis and 10 with portal vein block) were randomly allocated to the sheath or free-hand technique. Although the former was associated with significantly less bleeding within the first 24 hr of injection (p less than 0.05) but more postinjection pain (p less than 0.05) and esophageal stricture, there was a trend toward earlier obliteration of varices. This was most marked over the first three courses of injection, and although frequency of rebleeding was not significantly less, none of the 11 episodes in the sheath group were fatal, compared to 5 of 15 bleeds in those injected by the free-hand technique (p less than 0.05).

A controlled clinical trial of cimetidine in the recurrence of variceal hemorrhage: implications about the pathogenesis of hemorrhage.

In a prospective randomized double-blind controlled trial, 51 patients, 16 with cirrhosis and 35 with extrahepatic portal hypertension all of whom presented with variceal bleeding, were given either long-term cimetidine in a dosage of 1.6 gm daily (24 patients) or placebo tablets (27 patients). Thirty-eight patients completed 2 years of treatment. For 16 patients with cirrhosis, there was no significant difference in the frequency of rebleeding between the cimetidine (62.5%) and placebo (75.0%) groups. Similarly, in 35 patients with extrahepatic portal hypertension, the frequency with which bleeding recurred in the cimetidine (37.5%) and placebo groups (36.8%) was not significantly different. Gastric acid and esophageal function studies, including basal acid output, lower esophageal sphincter pressure, esophageal acid reflux, and clearance measurements, showed no significant differences between patients with cirrhosis or extrahepatic portal hypertension both before and after variceal bleeding and in healthy control subjects. These results suggest that it is unlikely that gastric acid reflux is a significant factor in the pathogenesis of variceal hemorrhage, and cimetidine does not prevent recurrent episodes of bleeding.

A prospective reappraisal of emergency endoscopy in patients with portal hypertension.

In a prospective study of emergency endoscopy in patients with portal hypertension and oesophageal varices referred to King's College Hospital with acute upper gastrointestinal bleeding, initial endoscopic examination on 90 separate consecutive hospital admissions carried out within 24 h of clinical haemorrhage showed active variceal bleeding in only 21 (23.3%) cases. Coexisting upper gastrointestinal lesions were present in 38.8% of examinations, but active bleeding from these sites was seen in only five cases (5.6%). Of the 64 cases in which no active bleeding was seen at initial endoscopy, 39 (60.9%) rebled during that admission, and repeat endoscopy in 27 of these, carried out within 1 h of this episode, revealed active variceal haemorrhage in 20 (74.1%) cases. These results indicate that variceal haemorrhage is intermittent, and, although bleeding may often stop spontaneously, a high proportion of patients subsequently rebleed, and this is invariably from varices rather than from coexisting upper gastrointestinal lesions. In addition, these findings confirm the importance of emergency endoscopy in making the correct decision about acute management.

Increased long-term survival in variceal haemorrhage using injection sclerotherapy. Results of a controlled trial.

Analysis of 107 patients with cirrhosis and recent variceal haemorrhage included in a prospective randomised trial of endoscopic injection sclerotherapy showed that in the sclerotherapy group 22 (43%) of the 51 patients had episodes of haemorrhage during the period of treatment, but in only 4 did bleeding occur after the varices had been obliterated. This contrasts with episodes of bleeding in 42 (75%) of the 56 patients receiving standard medical management-a highly significant difference. The overall risk of bleeding per patient-month of follow-up was reduced threefold with sclerotherapy. Of 22 patients followed up for at least one year after obliteration of varices, 14 had no evidence of reappearance of varices within this period and, by means of cumulative life-analysis tables, survival was shown to be significantly improved in the sclerotherapy group.

Recurrence of primary biliary cirrhosis after liver transplantation.

Three patients who had undergone orthrotopic liver transplantation for primary biliary cirrhosis and were being maintained on immunosuppressive therapy were investigated 31/2 to 41/2 years later because of the redevelopment of pruritus and mild jaundice. In one patient pigmentation was again evident, and all three had a rise in the titer of serum mitochondrial antibody after an initial fall. Liver histology showed features of primary biliary cirrhosis with non-suppurative destructive cholangitis, lymphoid aggregates, and increased deposition of copper-binding protein in the absence of cholestasis. None of these features was found in patients who had received grafts for other conditions and had lived for comparable periods, nor were they found in patients who had had rejection with bile-duct abnormalities. The overall findings indicate a recurrence of primary biliary cirrhosis in the donor organ.

Cyclosporin A in cadaveric organ transplantation.

The use of cyclosporin A (CyA) with a protocol designed to avoid the effects of nephrotoxicity resulted in a one-year survival of 86% in recipients of renal allografts from unmatched cadaveric donors. The drug also controlled rejection of liver and pancreatic allografts. It was possible to change patients initially treated with CyA to azathioprine and corticosteroids and vice versa, thus enlarging the potential value of CyA in organ allografting. Of 34 recipients of renal allografts, 29 were currently receiving only CyA as immunosuppressive treatment. Twelve patients never required any adjuvant steroid treatment. These results suggest that CyA is an effective immunosuppressant, and if used with care side effects need not be severe.

Liver biopsy as a day-case procedure: selection and complications in 200 consecutive patients.

The selection of 200 consecutive patients who underwent liver biopsy as a day-case procedure and subsequent complications were reviewed, In 59 patients a diagnosis of cirrhosis was confirmed by histological examination. Six patients developed minor complications attributable to the procedure and had to stay longer in hospital, and another returned with abdominal pain the evening after the biopsy. With careful selection of patients, liver biopsy may be safely undertaken on a day-case basis.

Prospective controlled trial of injection sclerotherapy in patient with cirrhosis and recent variceal haemorrhage.

64 patients with cirrhosis and recent variceal haemorrhage were studied in a prospective randomised trial of injection sclerotherapy by means of a flexible oesophageal sheath. 12 (33%) of the 36 patients in the sclerotherapy group, suffered further bleeds from varices compared with 19 (68%) of the 28 patients receiving standard medical treatment. The risk of bleeding per patient-month of follow up decreased more than threefold with sclerotherapy and the number of patients rebleeding after 2, 6, and 12 months was significantly reduced (p < 0.05). 1-year survival without further bleeding improved significantly with sclerotherapy (46% compared with 6%, p < 0.02), although the difference in overall survival assessed by cumulative life-table analysis was not statistically significant. The main complication of the technique was the development of oesophageal ulcers in some patients.

Survival and rehabilitation after orthotopic liver transplantation.

Between May, 1968, and April 27, 1980, 94 patients have been treated by orthotopic liver transplantation. During this time operative techniques and the management and selection of patients have changed. Healing of the biliary-tract anastomoses has been better since the introduction of a gallbladder conduit procedure and early irrigation of the donor biliary tract largely prevents damage to biliary-tract mucosa and sludge formation. Partial cardiopulmonary bypass in selected cases can provide control of the circulation during surgery. Many patients have been operated on too late, and an earlier selection is indicated. Of the 94 patients, 18 lived for over one year and 11 for two years, with 2 surviving for more than five years. 13 patients are currently alive. Rehabilitation of long-term survivors has been excellent, and although tumour recurred in more than 60% of patients grafted for primary hepatoma, worthwhile palliation can still be achieved.

The indications for and results of liver transplantation.

The overall indications for liver transplantations are becoming clearer. Patients with decompensated cirrhosis are poor risks and grafting should be done earlier. Results of transplants for primary biliary cirrhosis and well compensated cirrhosis are more encouraging. Transplantations for hepatocellular carcinoma is faced with the problem of high recurrences postoperatively. The presence of hepatitis B in a recipient is no longer a contraindication to grafting since this can be adequately treated with specific immunoglobulin. The latest introduction of Cyclosporin as an immunosuppressant may be of real benefit in liver transplantations.

[1-14C]Ethanol breath test in alcoholic liver disease.

The activity of ethanol metabolising enzymes was assessed in 51 patients with alcoholic and non-alcoholic liver disease using tracer doses of [1-14C]ethanol and measuring 14CO2 excretion in the breath. Alcoholic patients with only fatty infiltration of the liver showed significantly increased activity compared with controls. Comparing alcoholic patients with cirrhosis and a serum albumin greater than 28 g/l, activity in those with a recent history of continued heavy drinking was significantly greater than in patients who had abstained from alcohol. In addition, both groups of alcoholic cirrhosis showed significantly more activity than patients with non-alcoholic cirrhosis. The activities of patients with acute alcoholic or viral hepatitis were normal when their prothrombin times were less than 7 sec prolonged, but were reduced when prolongation exceeded 7 sec. These results demonstrate that in chronic alcoholic liver disease, even with cirrhosis, alcohol can still increase the activity of ethanol oxidising enzymes provided hepatic function remains adequate. However, this response is lost in acute liver damage and in chronic alcoholic disease with severe hepatic dysfunction.