The effect of introducing endoscopic therapy on surgery and mortality rates for peptic ulcer hemorrhage. A single center analysis of 1,125 cases.

The introduction of early endoscopic diagnosis has not been associated with a reduction in either surgical intervention or overall mortality for peptic ulcer hemorrhage. Recent studies have suggested that endoscopic therapy can reduce rebleeding rates from peptic ulceration. We report a 2-year experience of the influence of endoscopic heater probe (HP) (Olympus CD 10Z) therapy on the outcome of patients admitted with peptic ulcer hemorrhage. Eight hundred and sixty-two patients admitted with peptic ulcer hemorrhage over a 5-year period (1978/9 and 1983/5) before endoscopic therapy (PRE-HP), and 263 patients admitted with peptic ulcer hemorrhage after introduction of endoscopic therapy (POST-HP: 1986-1988) were assessed. All 1,125 patients were managed by a joint physician/surgeon team. The introduction of HP therapy was associated with a reduction in surgical intervention and overall mortality rates for gastric ulceration from 16% and 8.9% PRE-HP to 7% and 2.6% POST-HP respectively (p less than 0.05). A similar but non-significant trend was noted for duodenal ulceration. The beneficial effects of HP therapy appear to be due to a reduction in the need for surgical hemostasis in patients with an ulcer base visible vessel. Our results suggest that a more widespread use of endoscopic therapy may result in an improved outcome from peptic ulcer hemorrhage.

Propranolol in the prevention of recurrent variceal hemorrhage in cirrhotic patients. A controlled trial.

A double-blind controlled study of long-acting propranolol in the secondary prevention of variceal hemorrhage was conducted in 81 cirrhotic patients. After the index hemorrhage, all patients were treated with injection sclerotherapy on one occasion to secure hemostasis and then randomized within 72 h to propranolol or placebo therapy which was continued for 2 yr. Study endpoints were severe recurrence of variceal hemorrhage or death. Forty-two patients did not fulfill the entry criteria for the study. Thirty-eight patients received propranolol of whom 18 (47%) had further hemorrhage, 14 died, eight had side-effects (2 withdrawals), and 3 did not complete follow-up. Forty-three patients received placebo of whom 33 (77%) had further hemorrhage, 19 died, 5 had side-effects (2 withdrawals), and 5 failed to complete follow-up. The median time from onset of hemorrhage to starting drug therapy was 6 days for both groups. Life table analysis showed an equivalent incidence of further hemorrhage in both groups over the first 60 days, following which the propranolol group did consistently better than the placebo group. There was a significantly lower incidence of rebleeding in modified Child's C patients receiving propranolol (39%) than those on placebo (90%). No statistically significant effect on mortality was seen. In this study, propranolol reduced the incidence of late recurrence of variceal hemorrhage in patients with cirrhosis.

Controlled trial of heater probe treatment in bleeding peptic ulcers.

A prospective randomized controlled trial of endoscopic heater probe therapy in bleeding peptic ulcers was performed to determine whether probe therapy can reduce rebleeding rates. Of 630 patients endoscoped for suspected upper gastrointestinal haemorrhage over a 16-month period, 166 (26 per cent) were found to have a peptic ulcer. Either minor or no stigmata of recent haemorrhage were found in 115 patients at the time of endoscopy. A single peptic ulcer with either active haemorrhage or a visible vessel was found in 51 patients, 43 of whom were entered into the trial. There were eight exclusions: four were inaccessible, one was a torrential haemorrhage and three were excluded for non-technical reasons. Patients were randomized to receive either heater probe (n = 20) or sham (n = 23) therapy. In actively bleeding ulcers, immediate haemostasis was achieved following probe therapy in 14 of 18 patients (78 per cent) compared with none of 21 having sham treatment (P less than 0.002). No rebleeding occurred in the probe therapy group (n = 20) compared with rebleeding in five of 23 sham treated patients (P = 0.05). Urgent surgery for haemostasis was required in three of the five sham treated patients who rebled. It is concluded that heater probe therapy may be effective in reducing rebleeding rates in peptic ulcers accessible to the endoscope.

Bleeding colonic varices controlled by propranolol.

A 64-year-old man with hepatic cirrhosis developed severe haemorrhage from oesophageal varices. He underwent a course of sclerotherapy injections which successfully obliterated the oesophageal varices and prevented further oesophageal bleeding. He later developed serious bleeding from a site in the region of the ascending colon; angiography and radionuclide imaging suggested that varices were present in that region. Therapy with oral propranolol was effective in preventing any recurrence of gastrointestinal bleeding.

Double-blind comparison of two dosage regimens of misoprostol in the treatment of duodenal ulceration.

A multicenter double-blind study was conducted in 416 patients (306 male, 110 female) with active endoscopically proven duodenal ulcers who were randomly allocated to receive the prostaglandin E1 methyl ester analog (Misoprostol/Cytotec), either in a dose of 400 micrograms twice daily (206 patients) or 200 micrograms four times daily (210 patients). No significant difference in the healing rates between the two groups was observed at four or eight weeks. In patients treated twice daily, the ulcer healing rate at four weeks for the intent-to-treat cohort was 124/205 (60.5%) and for the evaluable cohort was 96/136 (69.1%). In patients treated four times daily, the healing rate was 124/207 (59.9%) for the intent-to-treat cohort and 96/148 (64.9%) for the evaluable cohort. Similarly, the healing rates achieved at eight weeks for the twice- and the four-times-daily dosages in the intent-to-treat cohort were 72.2% and 74.4%, respectively, and for the evaluable cohort were 88.0% and 86.6%, respectively. Significantly more patients receiving misoprostol twice daily were free of ulcer pain after four weeks of treatment than were those receiving misoprostol four times daily, namely, 71.4% as compared with 57.9%, respectively (P = 0.003) and for a median period of 21 as compared with 17 days (P = 0.002). Diarrhea was more common in patients receiving the drug twice daily, (15.5%) than in those treated four times daily (5%) (P = 0.001). Diarrhea, three or more stools daily, was often transient and self-limiting and only necessitated withdrawal from the trial in nine (4.4%) of those treated with misoprostol twice daily and in one patient (0.5%) of those treated four times daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced oral bioavailability of meptazinol in cirrhosis.

Kinetic analysis was carried out after single intravenous (25 mg) and oral (200 mg) doses of the novel partial opioid agonist meptazinol (Meptid) in patients with non-cirrhotic liver disease (NCLD) and biopsy proven cirrhosis. Comparison was made with a group of patients with normal hepatic function. Elimination half-lives after the intravenous dose were slightly prolonged in the cirrhotics (n = 10; 4.2 +/- 0.6 h) compared with the control (n = 8; 2.7 +/- 0.2 h: p less than 0.05) and NCLD (n = 8; 3.2 +/- 0.5 h) groups. There was no significant difference in meptazinol plasma clearance between the groups (cirrhotics = 72 +/- 8 l/h; NCLD = 89 +/- 9 l/h; control = 83 +/- 10 l/h). After the oral dose, seven of 15 cirrhotic patients vomited but only one patient in each of the other groups was unable to tolerate the drug (p = 0.06). This may be explained by very much higher peak meptazinol concentrations in the cirrhotic (n = 8; 184 +/- 37 ng/ml, p less than 0.01) and NCLD (n = 8; 131 +/- 38 ng/ml, p less than 0.05) patients than those of the controls (n = 7; 53 +/- 12 ng/ml) reflecting a mean four-fold and two-fold increase in oral bioavailability respectively (cirrhotics: n = 8; 27.9 +/- 5.3%: p less than 0.001; NCLD: n = 7; 13.7 +/- 3.9% p less than 0.05; controls: n = 7; 6.5 +/- 1.3%). There was no evidence of accumulation after chronic dosing with 200 mg meptazinol four times daily for 13 doses in seven control, seven NCLD and six cirrhotic patients. There were no detectable differences in psychomotor function measured objectively using the Leeds Psychomotor Tester of subjectively by linear analogue scoring between the groups in all three parts of the study. The oral use of meptazinol in patients with chronic liver disease is associated more with the development of nausea and vomiting rather than excessive sedation. These data suggest that dosage reduction in cirrhotic patients is advisable particularly if the drug is taken by mouth.

Antipyrine metabolism in acute hepatic porphyria in relapse and remission.

Antipyrine kinetics following a single oral dose were obtained in porphyric patients in attack and in remission and in controls. The clearance of antipyrine was significantly lower during an acute porphyric attack (median: 0.34 ml min-1 kg-1; range: 0.1-0.71, P less than 0.05) than in patients in remission (median: 0.53 ml min-1 kg-1; range: 0.28-0.87) or controls (median: 0.52 ml min-1 kg-1; range: 0.32-0.93). There was a significant negative correlation between weight-adjusted antipyrine clearance and the urinary excretion of the porphyrin precursors, delta-aminolaevulinic acid (r = 0.86, P less than 0.001) and porphobilinogen (r = 0.82, P less than 0.002). These data suggest that the more severe the porphyric attack, the greater the impairment of hepatic monooxygenase activity.

Dose related in vitro effects of ranitidine and cimetidine on basal and ACTH-stimulated steroidogenesis.

Isolated bovine adrenocortical cells were incubated with and without 3 ng/ml ACTH, with various concentrations (10-1000 micrograms/ml) of either cimetidine or ranitidine. Cortisol, corticosterone, and deoxycorticosterone outputs were measured. Cimetidine and ranitidine at 320 and 1000 micrograms/ml inhibited ACTH-stimulated corticosterone and cortisol synthesis and cimetidine decreased basal cortisol synthesis. The inhibitory effects of cimetidine on cortisol synthesis were approximately 10 times greater than those of ranitidine. Cimetidine (1000 micrograms/ml), but not ranitidine increased deoxycorticosterone synthesis by ACTH-stimulated cells, indicating inhibition of 11 beta-hydroxylation in the adrenal steroidogenic pathway. Although doses of cimetidine and ranitidine which produce these in vitro effects are much greater than plasma concentrations in normal clinical use, they might be important in acutely ill patients given intravenous bolus injections of cimetidine, or if either antagonist were accumulated by the adrenal to produce high intracellular concentrations.

Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis.

Midazolam kinetics and psychomotor function were studied after an intravenous dose of 0.075 mg/kg body weight in seven patients with alcoholic cirrhosis and eight control patients. Four of the seven cirrhotics died of complications of their liver disease within six months of the study. The metabolism of midazolam was significantly impaired in the cirrhotic patients (p less than 0.025). These patients also had evidence of greater sedation than the control group for up to six hours after the dose was administered (p less than 0.05). The clearance of midazolam did not correlate significantly with the serum albumin, or bilirubin, or with the kinetics of antipyrine, or indocyanine green. This study shows significant delay in the elimination of midazolam and decreased psychomotor function in patients with severe alcoholic liver disease. Caution is needed in using this drug for premedication in such patients before endoscopy.

Breast cancer in women with primary biliary cirrhosis.

The occurrence of extrahepatic malignancy was studied in 195 unselected patients who satisfied predetermined biochemical, immunological, and histological criteria for the diagnosis of primary biliary cirrhosis. The incidence of breast cancer in women with primary biliary cirrhosis was found to be significantly higher than in an age and sex matched control population from the same well defined geographical area (p less than 0.0015). The association of breast cancer and primary biliary cirrhosis remains unexplained, though diminished immunological surveillance, fat soluble vitamin deficiency, or endocrine dysfunction may play a part.

Use of perchlorate to block gastric uptake of free 99Tcm in the investigation of gastrointestinal bleeding.

The use of perchlorate to block gastric uptake of free 99Tcm-pertechnetate after in vivo labelling of red cells was investigated. In 19 out of 20 cases there was no evidence that previous administration of perchlorate adversely affected red cell labelling using commercial stannous agents. Adequate scintigraphic images of the vascular system could be obtained for up to 24 h after the cells were labelled. The technique was found to be of value in the investigation of sites of gastrointestinal bleeding.

Hepatic metabolic function in patients receiving long-term methotrexate therapy: comparison with topically treated psoriatics, patient controls and cirrhotics.

Standard biochemical liver function tests and the clearances of antipyrine and indocyanine green have been compared in psoriatic patients taking methotrexate, psoriatic patients on topical treatment, patient controls and patients with hepatic cirrhosis. The methotrexate-treated patients showed significant elevations in alkaline phosphatase (p less than 0.025) and gamma glutamyl transpeptidase activities (p less than 0.05) compared to topically treated psoriatics and patient controls. The clearance of antipyrine was reduced in the methotrexate treated group but not significantly (p less than 0.1 greater than 0.05). In contradistinction, the weight-adjusted clearance of indocyanine green was significantly impaired in the methotrexate group in comparison with the topically treated psoriatics (p less than 0.01). The clearance of both antipyrine and indocyanine green were markedly lowered in the cirrhotics (p less than 0.001 against all other groups). These data suggest that the serial measurement of alkaline phosphatase and indocyanine green clearance may provide a non-invasive indicator of the development and progression of methotrexate-related liver injury.

A double-blind randomized trial of cimetidine in acute upper gastrointestinal bleeding.

Two hundred and thirteen patients were studied in a double-blind trial of cimetidine versus placebo in the treatment of acute upper gastrointestinal haemorrhage. One hundred and six patients were randomly allocated to receive cimetidine and 107 to receive placebo. There was no significant reduction in transfusion requirements, incidence of further haemorrhage, length of stay in hospital, or mortality in the treated group. There was no subgroup of patients with acute upper gastrointestinal bleeding which appeared to benefit from treatment with cimetidine.

Familial occurrence of primary sclerosing cholangitis and ulcerative colitis.

Members of three families had primary sclerosing cholangitis and chronic ulcerative colitis. In each family, two siblings were affected; in one instance, they were twin brothers. All six individuals had primary sclerosing cholangitis and five also had ulcerative colitis. These cases represent the first reported instances of the familial occurrence of both primary sclerosing cholangitis and chronic ulcerative colitis; illustrate the typical clinical, laboratory, radiologic, and pathological features of primary sclerosing cholangitis; and support the hypothesis that genetic factors may play a role in the etiology of this obscure disorder.

A case of longstanding primary sclerosing cholangitis.

A 45-year-old man is described in whom there is currently ERCP and histological evidence of primary sclerosing cholangitis (PSC). A liver biopsy obtained 29 years ago shows similar histological features confirming that he had PSC at that time. This case indicates that PSC may follow a relatively benign course.

Endoscopic transmission of hepatitis B virus.

Although transmission of hepatitis B virus (HBV) infection has long been recognised as a potential hazard of gastrointestinal endoscopy, there has been little evidence of direct patient-to-patient cross-infection after such procedures. We wish to report a case of type B viral hepatitis almost certainly acquired at endoscopy from an instrument sterilised in the conventional manner, but which had been used on the previous day on a patient with bleeding oesophageal varices who was incubating type B viral hepatitis.

Primary biliary cirrhosis: an increased incidence of extrahepatic malignancies?

In a retrospective review of 85 patients with primary biliary cirrhosis (PBC), 10 (11.8%) were noted to have extrahepatic malignant neoplasm. In seven female patients the tumour developed within a mean of 3.5 yr after the clinical onset of PBC. This observed number of tumours, 3.5 times more common than the expected age-adjusted incidence, was statistically significant at the 0.5% level.