W. H. J. Summerskill

Relations between Pancreatic Enzyme Outputs and Malabsorption in Severe Pancreatic Insufficiency

Abstract To investigate the functioning reserve capacity of the exocrine pancreas, we studied the relations of steatorrhea and creatorrhea to lipase and trypsin outputs in 17 patients with chronic ...

Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared.

Among 120 consecutive patients with chronic active liver disease (CALD) randomized to different treatments, those receiving maintenance doses of prednisone 20 mg daily (Pred), prednisone in doses given on alternate days and titrated to secure resolution of clinical and biochemical abnormalities (Pred-Titrad), or a combination of prednisone 10 mg and azathioprine 50 mg daily (Comb) survived and underwent resolution of clinical and biochemical features of disease more often than a control group receiving placebo or azathioprine 100 mg daily. Histological remission occurred significantly more often with Pred and Comb than with other regimens. Major side-effects of therapy were commoner with Pred than with Comb or Pred-Titrad, which did not differ. We conclude that Comb is the initial treatment of choice for CALD, since clinical, biochemical, and histological resolution of disease activity occurs as often as with Pred, whereas early side-effects are significantly less frequent.

Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy

In 50 patients with chronic active liver disease, observer and sampling error in histologically evaluating hepatitis and cirrhosis after blind-needle biopsy of the liver was assessed from coded tissue. This was done by repeated readings of the same specimens by the same pathologist, by sequential biopsies from the same patients with cirrhosis, and by multiple simultaneous biopsies from adjacent areas of the liver. Observer error was small. The consistency of grading the individual histologic characteristics of hepatitis was 90%, and the reproducibility of the degree of either hepatitis or cirrhosis was 94%. Sampling error was also trivial in hepatitis, indicating that a single needle biopsy accurately reflects the type and degree of inflammation and necrosis in adjacent areas of the liver. By contrast, sampling error was of considerable magnitude when the presence of cirrhosis in patients known to have the lesion was sought, since confirmation by simultaneous or sequential biopsies was made in only 33% of the cases.

Pancreozymin bioassay in man based on pancreatic enzyme secretion: potency of specific amino acids and other digestive products.

The ability of products of digestion to stimulate pancreozymin secretion in man was investigated using a bioassay procedure, based on duodenal perfusion, which quantified the total outputs of pancreatic enzymes evoked by intraduodenal stimuli under steady-state conditions. Patterns of response resulting from physiologic intraduodenal concentrations of test material were basal output (with isotonic saline), washout of enzymes (with dextrose, micellar fatty acid, and amino acids), and sustained output of enzymes (with amino acids and micellar fatty acid). The sustained secretion of pancreatic enzymes found during the 2nd hr of perfusion and subsequently was characteristic of pancreozymin-induced secretion. The enzyme output in response to a mixture of essential and nonessential amino acids was significantly higher than that evoked by micellar fatty acid and was comparable with that resulting from the maximally tolerated dose of pancreozymin given by vein. Perfusion with essential amino acids caused enzyme outputs comparable to those induced by perfusion with the original amino acid mixture, whereas perfusion with nonessential amino acids had no effect. When the essential amino acids were tested individually, only phenylalanine, methionine, and valine caused significant increases in pancreatic enzyme output; the effect of tryptophan was indeterminate. However, the pancreatic enzyme output was less in response to these three essential amino acids than to mixtures containing all of them.

Simultaneous Measurements of Total Pancreatic, Biliary, and Gastric Outputs in Man Using a Perfusion Technique

A method, featuring perfusion of both gastric and duodenal markers with collections from the stomach and duodenum, was developed and validated for simultaneous measurements of total duodenal and gastric secretory outputs in man. Calculations of duodenal reflux into the stomach, of contamination of duodenal contents by gastric contents, and of the amounts -recycled between the two organs were made. The values so obtained were used to establish application of duodenal perfusion (with simultaneous gastric aspiration) for precise measurements of total secretions into the duodenum by simple calculations. The technique was used to show that total pancreatic enzyme output after intraduodenal stimulation by perfused amino acids was identical with that obtained after a maximally tolerated dose of pancreozymin given by vein. However, simultaneous intraduodenal and intravenous stimulation caused a pancreatic enzyme output significantly exceeding either method of stimulation alone, or any previously reported, thereby suggesting that conventional stimuli cannot attain maximal secretory capacity for enzymes. When applied to determination of total bilirubin output in the duodenum, the results approximated those reported by other methods.

Profile of Gastric Potential Difference in Man: Effects of aspirin, alcohol, bile, and endogenous acid

Measurement of transmural potential difference (PD) of the human stomach using a reference electrode placed in a peripheral vein showed that PD was higher in the body of the stomach than in the antrum. Stimulation of gastric acid secretion by betazole caused only a trivial and temporary decrease in PD below the basal value, the decrease occurring shortly after the stimulus was injected and prior to the onset of peak acid output. The administration of acetylsalicylic acid, alcohol, or duodenal contents rich in bile and pancreatic enzymes all caused rapid and profound reductions in gastric PD. Maintenance of gastric PD may be a sensitive indicator of mucosal integrity in man, since changes in PD occur with agents shown to cause damage by other methods in other species.

Chronic active liver disease: The range of histologic lesions, their response to treatment, and evolution

Abstract Histologic study of serial biopsy specimens in a prospective, controlled, double blind, randomized trial of treatment involving 63 patients with predefined clinical and biochemical criteria of severe chronic active liver disease revealed five different histologic patterns of hepatic injury on initial biopsy: chronic persistent hepatitis, chronic aggressive hepatitis, subacute hepatitis with bridging, subacute hepatitis with multilobular necrosis, and cirrhosis. The initial biopsies in the fatal cases revealed cirrhosis, subacute hepatitis with multilobular necrosis, or subacute hepatitis with bridging. Patients with subacute hepatitis with bridging and with multilobular necrosis more frequently revealed stigmata of viral hepatitis and more frequently developed cirrhosis than chronic aggressive hepatitis, regardless of treatment. The severe forms of hepatitis more frequently remitted to the histologic features of chronic persistent hepatitis in patients treated with prednisone and a combination of prednisone and azathio-prine than with azathioprine or placebo alone. Serial biopsy specimens frequently revealed changes in the histologic pattern before remission to chronic persistent hepatitis. Histologic progression to cirrhosis may occur by bouts of intralobular and multilobular necrosis as well as by piecemeal necrosis. Sampling error in needle biopsy of cirrhosis is so great that the condition either may be missed or may be impossible to accurately classify into portal and postnecrotic cirrhosis. Observations at autopsy always revealed postnecrotic cirrhosis characterized by extensive parenchymal loss and incomplete regeneration. We conclude that the evolution of any lesion is influenced by at least two factors: the original histologic pattern and the therapy applied.

Assessment of Activity in Chronic Active Liver Disease: Serum Bile Acids Compared with Conventional Tests and Histology

Abstract Serum conjugates of cholic acid were determined by radioimmunoassay and compared with conventional tests in 38 patients during the course of chronic active liver disease that responded to treatment; 16 patients subsequently relapsed when treatment was discontinued. At the time of diagnosis, values for these bile acids were always significantly elevated. At biochemical resolution of conventional liver tests, the values were still elevated in 33 of 38 patients, and this finding correlated well with evidence of continuing histologic activity. At histologic remission of disease activity, these values were less than twice the upper limit of normal in all 22 patients who subsequently remained in remission without treatment, but were significantly higher in nine of 16 who later relapsed. During relapse, serial determinations showed that elevation of serum conjugates of cholic acid preceded an increased glutamic oxalacetic transaminase. Serum concentrations of these bile acids in chronic active liver dis...

Different gastric, pancreatic, and biliary responses to solid-liquid or homogenized meals.

We have compared responses to an ordinary solid-liquid (S) meal and to a homogenized (H) meal of identical composition (sirloin steak, bread, butter, ice cream with chocolate syrup, and water) by measuring simultaneously postprandial gastric, pancreatic, and biliary functions by marker-perfusion techniques. Responses to each (S or H) meals differed strikingly both in magnitude and pattern. S meals elicited a stronger early gastric secretory response (acid, pepsin, and volume) which compensated for faster initial emptying and resulted in higher gastric acidity and volume than after H meals. Further, nutrients ingested with S meals were emptied at a slower rate than H (as evidenced by a more gradual decline in intragastric buffer and osmolality, as well as time required for complete emptying of the meal). This, in turn, prolonged pancreatic and biliary responses since stimulation of these organs continued for as long as meal was delivered into the duodenum. However, early biliary outputs (gallbladder response) were less after S than H, probably because nutrients entered the duodenum more slowly and were initially diluted by rapidly emptying water. The physical characteristics of each meal (encompassing appearance, taste, and form of ingestion) probably accounted for early differences in digestive responses. Later, interactions between gastric (motor and secretory), pancreatic, and biliary functions played a major role. Our findings suggest that gastric, pancreatic, and biliary responses to liquid test meals introduced into the stomach may differ substantially from the presumably more physiological response to ordinary solid-liquid meals.

Contrasting features and responses to treatment of severe chronic active liver disease with and without hepatitis BS antigen.

To determine the clinical implications of HBSAg in severe chronic active liver disease (CALD), patients with HBSAg positive CALD were compared with those chosen by identical clinical, functional, and morphological criteria in whom this test and anti-HBS were negative. HBSAg positive patients were predominantly males over 40 years of age and more frequently failed to respond to conventional treatment programmes with prednisone. HBSAg negative patients were more often female and younger, had a higher incidence of associated immunopathic disease and immunoserological markers in high titre, and more often responded to treatment with full remission of their disease. HBSAg positive patients failing treatment with conventional doses of prednisone often improved with higher doses, but did not reach full remission of their disease. The benefit-risk ratio of both conventional and high doses of prednisone in HBSAg positive severe CALD needs further clarification.