It has been suggested that hepatic encephalopathy could be due to the accumulation of false neurotransmitters and that the administration of a neurotransmitter precursor such as L-dopa would be beneficial to cirrhotic patients with hepatic encephalopathy. A prospective randomized controlled study was carried out to determine whether L-dopa has any effect on the course of cirrhotic hepatic encephalopathy. L-Dopa, L-Dopa and dopa-decarboxylase inhibitor, or placebo was given orally for 7 days to 75 cirrhotic patients with hepatic encephalopathy. The effect was assessed by clinical parameters as well as serial electroencephalograms. There was no statistically significant difference with respect to clinical improvement or deterioration in patients treated with either L-dopa or L-dopa and dopa-decarboxylase inhibitor or placebo. It is concluded that L-dopa is ineffective in the treatment of cirrhotic hepatic encephalopathy. Inefficacy was not due to late onset of treatment, to poor intestinal absorption of L-dopa, to destruction of L-dopa in the blood, or to impaired passage of L-dopa into the cerebrospinal fluid.

The therapeutic efficacy of bismuth subsalicylate was examined in a randomized double-blind fashion in 59 volunteers who were inoculated with Norwalk agent. Sixty-eight percent of the volunteers demonstrated seroconversion; 57% became ill. The severity and duration of the illness in 32 volunteers in the treatment and placebo groups were compared. Significant reduction in the severity and duration of abdominal cramps (P less than 0.01) and in the median duration of GI symptoms (P less than 0.05) was noted in the treatment group. There was no difference in the number, weight, or water content of stools, or in the rate of viral excretion between the two groups. The median duration of illness was 20 hr in the treatment group and 27 hr in the placebo group (0.1 greater than P greater than 0.05).

The present study was undertaken to determine whether or not spironolactone could induce drug-metabolizing enzymes in patients with ascites due to alcoholic cirrhosis of the liver. The disposition of antipyrine was therefore studied in 15 patients with cirrhosis before and after 13 days of spironolactone treatment (200 mg/day) and in 15 comparable patients not treated by spironolactone. In spironolactone-treated patients, a 40% increase in elimination rate constant of antipyrine (P less than 0.01) was due both to a decrease in apparent volume of distribution by 11% (P less than 0.01) and to a 20% rise in metabolic clearance rate (P less than 0.01). In control patients treated with furosemide or by paracentesis no significant change in metabolic clearance rate of antipyrine was found. As with spironolactone, furosemide decreased the apparent volume of distribution (9%, P less than 0.05) in proportion to the loss in body weight. Since spironolactone treatment was not associated with improvement in the fractional clearance of bromosulfophthalein, nor in serum albumin, prothrombin time, and factor V, the data are compatible with the idea that even in cirrhosis the hepatic drug-oxidizing enzymes were induced by spironolactone. Thus, the consequences of enzyme induction should be considered when spironolactone is associated with other drugs for the treatment of cirrhotic patients.

Steatorrhea persists in most cystic fibrosis patients with exocrine pancreatic insufficiency despite enzyme replacement, perhaps because gastric acid inactivates oral enzymes. Bile acid malabsorption may parallel steatorrhea. We studied the effect of adding cimetidine (300 mg a.c.) to pancreatic enzyme therapy in 8 patients with cystic fibrosis and steatorrhea. Fecal bile acid, weight and fat, and postprandial serum bile acids were measured with and without cimetidine. D-Xylose absorption was normal in all patients. On constant diets, 72-hr stools were collected during enzyme therapy and during a 5-day course of enzymes plus cimetidine. Addition of cimetidine to enzyme decreased fecal weight (257 +/- 32.6 to 198.6 +/- 32.5 g/day), increased the percent of dietary fat absorbed (75.0 +/- 4.9 to 80.1 +/- 4.1%, P less than 0.05), but had no effect on fecal bile acids (4.7 +/- 0.9 to 4.2 +/- 1.0 mmol/m2/day). Compared with no therapy, enzymes increased postprandial serum bile acid at 60 min (9.56 +/- 1.0 to 14.0 +/- 1.3 muM/liter, P less than 0.05) and at 120 min (9.4 +/- 1.2 to 12.4 +/- 1.6 muM/liter, P less than 0.02). The addition of cimetidine to enzymes abolished this postpranidial bile acid rise. In conclusion, addition of cimetidine to oral pancreatic enzyme therapy decreases stool weight and fat but perhaps not stool bile acids in cystic fibrosis. However, correction of fat absorption is incomplete. Enzyme therapy increases postprandial serum bile acids, and this increase is abolished with oral cimetidine. In view of the incomplete correction of steatorrhea and the alterations in serum bile acids induced by cimetidine, further research with this new medication is needed before it can be recommended for routine clinical use in patients with cystic fibrosis.

The effects of azathioprine on the course of primary biliary cirrhosis were studied prospectively in a multinational, double-blind randomized clinical trial involving 236 patients, of which 124 received azathioprine and 112 placebo. No significant effects were seen on survival, clinical course, hepatic histologic features, hepatic tests, or immunologic abnormalities after a median follow-up period of 18 mo, but most of the trends observed were in favor of azathioprine. The results obtained so far indicate that the effect of azathioprine as a single treatment is limited and probably of little clinical importance, but more years of follow-up will be needed to provide a definite conclusion.

Six patients with cirrhosis and severe chronic hepatic encephalopathy were treated with bromocriptine. All showed significant overall improvement clinically and in 3, the electroencephalogram became normal. The cerebral blood flow increased significantly from 32.7 +/- 2.4 (mean +/- 1 SE) to 40.5 +/- 1.5 ml/100 g brain/min (P less than 0.05). Similarly, there were significant improvements in the cerebral oxygen consumption from 2.2 +/- 0.4 to 3.3 +/- 0.4 ml/100 g brain/min (P less than 0.02) and in cerebral glucose consumption from 2.1 +/- 0.6 to 6.6 +/- 1.6 mg/100 g brain/min (P less than 0.02). Cross-over to placebo produced overall deterioration, more marked in the patients who had received the active drug for the shorter time period. No serious side effects were seen; the drug was well tolerated in doses of up to 15 mg daily and is a useful treatment for chronic hepatic encephalopathy when the response to conventional therapy has been poor.

Nonsteroidal antiinflammatory drugs (NSAID) induce the formation of bleeding gastric and intestinal ulcers in experimental animals. The damage can be prevented by prior local administration of prostaglandins, indicating that prostaglandins have protective properties on the gastrointestinal mucosa. The protective effect was studied in humans by measuring the fecal blood loss during indomethacin treatment of 18 patients with rheumatic diseases with and without concomitant oral supplementation with 1 mg prostaglandin E2 three times daily. The study had a randomized double-blind crossover design using 51Cr-labeled erythrocytes as marker of gastrointestinal bleeding. Indomethacin increased the daily fecal blood loss from 1.0 +/- 0.3 to 2.8 +/- 0.6 ml (P less than 0.005). When oral PGE2 was taken concomitantly, the blood loss was reduced to 1.1 +/- 0.2 ml daily (P less than 0.01), i.e., to the control level. Side effects of prostaglandin E2 were negligible, and the beneficial effect of indomethacin on joint status and symptoms was not interfered with. No changes were recorded in repeated blood tests except for a slightly reduced hemoglobin and a small but statistically significant reduction of serum-calcium during indomethacin treatment, an effect hitherto not described in normocalcemic human subjects. A protective effect on the gastrointestinal mucosa by oral prostaglandin E2 has by the present study been demonstrated also in humans. The protection is unrelated to the gastric acid secretion, which is not inhibited by oral prostaglandin E2. The finding may have clinical application, as gastrointestinal side effects and bleeding are common reasons for discontinuation of NSAID in patients with rheumatic diseases.

Fifteen patients with chronic diarrhea and fecal incontinence were admitted to a clinical research center and treated for 3 days with either placebo or diphenoxylate with atropine (Lomotil). The patients were then crossed over to the alternate medication. Lomotil had no effect on rectal or anal sphincter pressure or on continence for saline that had been infused into the rectum. However, Lomotil therapy reduced average stool frequency (from 4.9 to 2.6 times/day) and average stool weight (from 460 to 256 g/day). These results suggest that temporary or intermittent therapy with Lomotil and related drugs might benefit patients with chronic diarrhea and fecal incontinence. They should do this by virtue of a reduction in stool frequency and stool volume, without a deleterious effect on the defense mechanisms against incontinence.

The cholelitholytic action of ursodeoxycholic acid (UDCA) was investigated by a double-blind clinical trial. The trial started with 151 subjects all confirmed by radiographic examination as having radiolucent gallstones in a functioning gallbladder. The subjects were divided into three groups receiving 600 mg/day of UDCA, 150 mg/day of UDCA, and placebo (lactose) per day, respectively. Seventy-nine cases were classed as dropouts or were excluded due to incomplete follow-up or inadequate patient selection, and the data on the remaining 72 cases were analyzed. After 6--12 mo of treatment, dissolution of decrease in size or number of stones occurred in 10 of the 29 cases in the 600 mg/day group (34.5%), 4 of 23 cases in the 150 mg/day group (17.4%), and 1 of 20 cases in the control group (5.0%). For those cases with noncalcified, less than 15 mm in diameter, and floating stones, efficacy increased to 83.3% in the 600 mg/day group. Lithogenic index of bile defined by Thomas and Hofmann became unsaturated after treatment in the 600 mg/day group. Neither diarrhea nor hepatic toxicity was noted. The results indicate that UDCA is a safe and effective litholytic agent.

Twenty-eight patients entered a double-blind controlled trial to evaluate the efficacy of prednisolone treatment in severe acute alcoholic hepatitis accompanied by encephalopathy. Fifty-three percent (8 of 15) given prednisolone and 54% (7 of 13) given placebo died during the study. The mean duration of hospitalization was 66 days for the prednisolone-treated group and 56 days for those treated with placebo. Prednisolone treatment produced no important beneficial effect on any of the hepatic biochemical tests. The outcome in any particular case was directly related to the development of specific lethal complications (renal failure, injection, and gastrointestinal bleeding) rather than to the treatment employed. We were unable to show any beneficial effect of prednisolone treatment on morbidity or mortality in patients with severe acute alcoholic hepatitis and encephalopathy.

Two comparative studies of six staining techniques in detection of Entamoeba histolytica in rectal biopsies were performed. The techniques evaluated were direct and indirect fluorescent antibody technique, and four conventional stains: PAS, H & E, Trichrome, and PTAH). On ethanol-fixed tissue, the direct fluorescent antibody technique was the most sensitive, detecting amoebas in 84% of rectal biopsies from 19 aspirate-positive dysentery patients. PAS staining was specific, almost as sensitive, and amoebas could be rapidly detected. The other three conventional methods, however, detected amoebas in only 53--58% of the aspirate-positive patients and required considerable efforts to find the amoebas. The indirect fluorescent antibody technique performed on ethanol-fixed tissues was comparable to the direct technique. The same technique used on formalin-fixed tissues had high background staining, but amoebas could still be detected more efficiently than with conventional staining. Following 20 hr or more treatment with metronidazole, no patient had amoebas detectable in their rectal biopsies by any technique used. Patients with amoebic dysentery and necrotic ulcers on protoscopy had amoebas detected more frequently in rectal biopsy than did patients with mild disease as determined by proctoscopy. Entamoeba histolytica in rectal biopsies can be detected most easily in ethanol-fixed tissue stained with either a fluorescent antibody or with PAS. If amoebas are not detected in the rectal biopsy, amoebic colitis cannot be excluded.

Gastroparesis is a relatively uncommon but clinically troublesome disorder that develops in some patients with diabetes mellitus or after gastric operations. Its pathogenesis remains obscure. We used a manometric technique to record pressure changes in fasting patients in the gastric fundus, distal stomach, and adjacent small bowel of patients with severe gastroparesis, asymptomatic diabetic patients, asymptomatic postsurgical patients, and healthy controls. Patients with gastroparesis had normal interdigestive motor cycles (phase III) in the intestine but not in the stomach. Sporadic motor activity in the stomach (phase II) also was markedly reduced. Metoclopramide and bethanecol significantly increased gastric motor activity in these patients, often triggering an intense burst of motor activity in the stomach, similar to phase III. These observations suggest that gastroparesis is a potentially reversible disorder and should encourage further attmpts for pharmacologic control of the syndrome.

A prospective study of the clinical pattern and course of primary biliary cirrhosis based on the data of 236 patients (211 females, 25 males) in an international randomized trial has been performed mainly using life-table technique. The median follow-up period has been 18 mo. After the entry into the study, at which time the median duration of symptoms was 2.1 yr, the estimated 5-yr increase in the cumulative percentage of patients was for pruritus from 75% to 95%, jaundice 59% to 82%, hepatomegaly 54% to 86%, pigmentation 54% to 85%, xanthomas 27% to 50%, GI bleeding 17% to 46%, ascites 7% to 49%, and vertebral collapse 3% to 20%. The frequency of cirrhosis increased from 30% to 82% in 4 yr. The mitochondrial antibody titer showed a high rate of progression with time. In analysis of subgroups, age, histologic stage, and particularly the serum bilirubin level were important prognostic factors. Sex, duration of symptoms, and character of first symptom or sign had no independent prognostic influence. The most important indication of seriously progressive course was rapid development of severe cholestasis independent of the histologic stage.

One of the potential complications of bile acid therapy for gallstone disease is the promotion of intestinal absorption of cholesterol, thereby increasing the influx of cholesterol in body pools. To determine whether bile acid feeding is associated with an increased absorption of intestinal cholesterol, absorption measurements were made in 8 obese subjects given chenodeoxycholic acid (CCDA) or Bilron (750 mg/day). The bile acids were given in random order, separated by control periods, in patients undergoing weight reduction. Absorption of cholesterol (mass and percent) and of bile acids were determined by a technique of combined measurements of biliary lipid secretion and fecal steroid excretion. Our data showed that during treatment with either bile acid, a marked increase in pool size and hepatic secretion of bile acids occurred. However, despite an increased flux of bile acids through the intestinal tract, there was no significant increase in cholesterol absorption as compared to control periods. Absorption rates during administration of the two bile acids were approximately the same. Furthermore, plasma cholesterol concentrations were stable throughout both control and treatment periods. Bile acid absorption remained highly efficient (greater than 96%) during all periods, even with administration of exogenous bile acids.

Among 569 patients with Crohn's disease, 24% had a history of at least one extraintestinal manifestation and 36% had a history of perianal disease before randomization. Multiple extraintestinal manifestations occurred in the same patient more frequently than would be expected by chance. Seventy-six percent of patients with ileocolitis had perianal disease, extraintestinal manifestations, or both. This was significantly greater than the 58% incidence in patients with disease confined to the small bowel. Perianal complications alone were significantly more common in patients with colitis or ileocolitis than in those with disease of only the small bowel. This was true also of internal fistulization. There was a significant positive association between perianal disease and the presence of extraintestinal features. Perianal abscess appeared to respond to sulfasalazine and anal fissure to prednisone or azathioprine. These results require confirmation in larger series of patients.