Comparative serum prednisone and prednisolone concentrations following administration to patients with chronic active liver disease.

Following administration of equivalent oral doses (30mg) of either prednisone or prednisolone to 5 patients with chronic active liver disease who had failed to respond to therapy, 5 patients with chronic active liver disease in remission induced by prednisone, and 7 healthy volunteers, corticosteroid concentrations were measured in both serum and urine by radioimmunoassay. Prednisone and prednisolone concentrations in the urine were very similar in all groups, regardless of the drug given. After either treatment, the peak serum concentration and area under the prednisolone serum concentration-time curve were 4 to 5 times those of prednisone. Slight differences among the 3 groups studied were seen in prednisone and prednisolone pharmacokinetics, but none was significant. It is concluded that the use of prednisone instead of prednisolone to treat chronic active liver disease can not be implicated as a cause of treatment failure. Indeed, this study suggests that either medication is effective, and this is supported by serum concentrations which suggest a rapid interconversion equilibrium between the 2 corticosteroids.

Clinical features and prognosis of severe chronic active liver disease (CALD) after corticosteroid-induced remission.

Disappearance of symptoms, resolution of most biochemical abnormalities, and histologic improvement to mild chronic inflammation were accomplished in 69 of 123 patients (56%) with severe chronic active liver disease treated with corticosteroids for up to 6.5 yr. Remission of at least 6 mo duration was possible in 35 of the 69 (51%) after discontinuation of therapy while others relapsed promptly and required retreatment. The likelihood of sustained remission was not predicted by initial clinical or biochemical features, although patients developing cirrhosis during treatment invariably relapsed. Subsequent courses of treatment after relapse were equally effective in again inducing remission, but the probability of another relapse increased after each successive therapy and was 86% after three treatments. Six of twenty-two patients (27%) followed for at least 4 yr after initial remission had three or more relapses. Although patients who relapsed were more likely to develop cirrhosis, manifestations of portal hypertension and immediate survival were not affected by relapse. Complete disappearance of all manifestations of active disease was possible in 12 of the patients entering remission (17%), but only patients without cirrhosis consistently sustained this improvement. We conclude that relapse after cessation of therapy frequently follows corticosteroid-induced remission of severe CALD, especially if cirrhosis develops, but does not jeopardize response to subsequent treatments or alter early prognosis.

Development and early prognosis of esophageal varices in severe chronic active liver disease (CALD) treated with prednisone.

The prevalence of gastroesophageal varices and gastrointestinal hemorrhage was determined in 124 patients with severe chronic active liver disease (CALD) receiving prednisone and followed regularly for up to 10 yr. Varices were demonstrated by contrast radiography in only 19 patients (15%). Ten had varices before therapy and nine developed them after 12-102 mo of observation (mean, 38 +/- 9 mo.). The likelihood of developing varices within 5 yr after therapy was 8% in all patients and 13% after documentation of cirrhosis. Hemorrhage from varices occurred in only 1 patient, who had varices and bled once before treatment. Bleeding from other sites was commoner in the presence of varices (P less than 0.025), but mortality was not increased by bleeding from any site. The probability of upper gastrointestinal bleeding was only 6% within 5 yr after therapy and the 5 yr survival was 93%. In severe CALD, varices are an uncommon initial finding and do not develop quickly or hemorrhage early after steroid therapy.

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.

Oral prednisone for chronic active liver disease: dose responses and bioavailability studies.

Serum concentrations of prednisolone were measured by radioimmunoassay after the administration of prednisone (10, 20, or 30 mg) by mouth to five healthy volunteers, five patients with severe chronic active liver disease (CALD), and five patients with CALD in remission induced by prednisone. Only minor differences were found between the groups and bioavailability was linearly related to the dose of prednisone (r = 0.993). After prednisone (10 mg) was given by mouth and by vein to similar groups of volunteers and 11 additional patients with CALD, bioavailability of oral prednisone approximated 100% of the intravenous dose and no differences were found in the pharmacokinetics of prednisolone. We conclude that prednisone is effectively absorbed and converted to prednisolone in health and CALD and find no pharmacological evidence that either drug would be superior to the other for treating CALD.

Cell-mediated cytotoxicity in chronic active liver disease: a new test system.

An in vitro cytotoxicity system was developed for studying patients with chronic active liver disease using as the target cells 51Cr-labeled avian erythrocytes coated with cell membrane lipoprotein extracted from human liver and, as the aggressors, mononuclear cells from peripheral venous blood. Approximately 50% of 62 patients with chronic active liver disease showed cytotoxicity in this test system as did 5% of 100 apparently healthy controls. In addition, mild cytotoxicity was shown by 2 of 8 patients with the primary biliary cirrhotic syndrome and 2 of 17 persons with other liver diseases. No specific antibody was added to the test system and the cytotoxicity could be inhibited by free lipoprotein, antilipoprotein, and by aggregated Ig. Cytotoxicity also was abolished by the depletion from the mononuclear cells of cells phagocytic for iron filings. The effect of depletion of these phagocytic cells was not restored by the addition of 2-mercaptoethanol. These findings add further evidence that autoimmune responses to liver tissue occur in many patients with chronic active liver disease and, importantly, suggest also that these may occur in some apparently healthy people.

Severe chronic active liver disease. Prognostic significance of initial morphologic patterns.

To determine the usefulness of recognizing the different morphologic patterns of chronic active liver disease (CALD), we compared clinical and biochemical features as well as responses to treatment in 32 patients with chronic active hepatitis (CAH); 36 with subacute hepatitis and bridging necrosis (SHB); 30 with subacute hepatitis and multilobular necrosis (SHMN); and 30 with cirrhosis and active hepatitis (Cirrh). The morphological lesions did not correlate with clinical or etiologic features. Patients with CAH had less severe biochemical abnormalities, entered remission more often, and failed to respond to treatment less frequently than those with SHMN or Cirrh. SHB and SHMN resembled each other in many regards and showed greater functional changes than CAH. Cirrhosis developed more often after SHMN than CAH and was associated with a poorer prognosis than CAH. Serial liver biopsies revealed all possible histologic transitions, with reduction of inflammation usually occurring in patients treated with steroids and extension of inflammation being more frequent in those not receiving these drugs. CAH, SHB, SHMN, and Cirrh, therefore, reflect the degree and extent of disease activity at any given time in CALD, rather than representing different conditions. Identification of the initial morphologic lesion is helpful because of differences in prognosis.

Gastric secretion and emptying after ordinary meals in duodenal ulcer.

We have studied the gastric response to an ordinary solid-liquid meal in 12 patients with active duodenal ulcer and 8 healthy volunteers. Our method employs gastric and duodenal markers to quantify acid, pepsin, and volume outputs in response to the meal, without manipulating intragastric pH. Intragastric volume, rate of gastric emptying, delivery of acid into the duodenum, and serum gastrin response were also measured simultaneously. On a separate day, peak acid output in response to betazole (1.5 mg per kg subcutaneously) was determined. Our results indicate an inappropriately prolonged gastric secretory response to meals in duodenal ulcer disease, without a concomitant increase in peak postprandial secretory rates or an increase in serum immunoreactive gastrin levels. Further, the stomach in duodenal ulcer disease did not "retain" the additional acid secreted in the later postprandial period, and abnormally high rates of acid delivery into the duodenum occurred. Our data are consistent with a dual defect in the duodenal mechanisms regulating both acid secretion and acid delivery into the duodenum.

Participation of the jejunum and ileum in postprandial gastric secretion in man.

The role of the small intestine in postprandial gastric secretory function was determined in 6 normal volunteers by diverting chyme at the ligament of Treitz and comparing the results with those obtained in the same individuals when chyme was exposed to the entire small intestine. Because diversion of chyme caused a lesser gastric secretory response, it is concluded that the small intestine contributes appreciably to the magnitude of gastric secretory responses to meals.

Prednisone for chronic active liver disease: pharmacokinetics, including conversion to prednisolone.

To determine the effect of impaired liver function on conversion of prednisone to prednisolone, and to investigate the relationship of this to responses to treatment with prednisone, we measured serum prednisone and prednisolone by radioimmunoassay after 10 mg of prednisone was given by vein to 10 healthy volunteers, 6 untreated patients with severe chronic active liver disease (CALD), 10 patients with prednisone-induced remission of CALD, and 3 patients with CALD deteriorating despite treatment with prednisone. Prednisone disappearance was comparable in all groups and substantial values for serum prednisolone appeared in all groups within 0.3 hr. Minor differences between the groups included lower than normal serum prednisolone in severe CALD and treatment failure; a higher percentage of nonprotein bound prednisolone in such patients; and an association between earlier treatment with prednisone and an increased disappearance rate of prednisolone. We conclude that no major defect of prednisone metabolism occurs in CALD and that failure of this condition to respond to therapy with prednisone is caused by other factors.

HLA determinants in chronic active liver disease: possible relation of HLA-Dw3 to prognosis.

Thirty-eight patients with severe chronic active liver disease (CALD) were found to have a significantly higher frequency of HLA-Dw3 (68%) than 91 healthy controls (24%) (P less than 0;0001). The association of CALD was statistically significantly stronger with the D locus than with the B locus of HLA. The response to treatment was significantly worse in patients with HLA-Dw3 than in patients who lacked this antigen.

Development of radioimmunoassays for prednisone and prednisolone. Application to studies of hepatic metabolism of prednisone.

Radioimmunoassays for measuring prednisone and prednisolone (delta1 corticosteroids) in serum have been developed. By using 6,7-3H-delta1 corticosteroids as tracer, rabbit antibodies against delta1 corticosteroid-21-hemisuccinate in bovine serum albumin, and ammonium sulfate precipitation, the assays detected less than 0.8 ng/ml of delta1 corticosteroid and interassay coefficients of variation were less than 8.5 %. The specificity of antibodies, tested against all drug metabolites and major endogenous steroids, showed that only 21-glucuronic acid esters of delta1 corticosteroids had cross-reactivity of possible clinical importance. Assays were validated by measuring levels in samples of fastingstate sera with or without adding known amounts of prednisolone. Measurements of serum concentrations of both prednisone and prednisolone in normal dogs and in those with hepatic vascular exclusion were made after intravenous administration of prednisone. Although high levels of prednisolone appeared rapidly in normal dogs, only slight amounts were measured in dogs with hepatic vascular exclusion, which emphasized the importance of the liver in the conversion of prednisone to prednisolone, its active metabolite.

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.

Responses to treatment can differentiate chronic active liver disease with cholangitic features from the primary biliary cirrhosis syndrome.

Of 125 patients fulfilling preestablished criteria for severe chronic active liver disease (CALD) and enrolled in a prospective trial of treatment, 15 (12%) presented with morphological features of liver biopsy consistent with the diagnosis of both CALD and primary biliary cirrhosis (PBC) syndrome. Customary clinical, biochemical, and immunoserological studies failed to distinguish fully between these conditions. By contrast, early response to treatment with prednisone and/or azathioprine identified two different groups of patients. Five patients failed to respond, whereas 10 improved and this was followed by resolution of all clinical, biochemical, and morphological evidence of disease activity. Analysis of the initial chemical findings and cumulative bile duct counts from multiple biopsies correlated failure to respond with biochemical and morphological features more consistent with PBC than CALD. Responses to treatment can therefore be utilized when indicated for differentiating CALD with cholangitic features from PBC.

Lymphocyte cytotoxicity and inhibition studied with autologous liver cells: observations in chronic active liver disease and the primary biliary cirrhosis syndrome.

A method is described for determining the cytotoxicity of normal and autologous lymphocytes for 51Cr-labeled isolated parenchymal liver cells in a low aggressor to target cell ratio. Results were compared from patients with chronic active liver disease (CALD), chronic persistent hepatitis (CPH), miscellaneous liver diseases, or primary biliary cirrhosis (PBC). In 53% of CALD patients, lymphocytes showed greater cytotoxicity for hepatic cells than did normal allogenic lymphocytes, but in 32% there was significantly less 51Cr release than normal; in the remainder, results were in the normal range. Lymphocyte cytotoxicity was greater in patients with disease of short duration and less in those treated with corticosteroids. In untreated CALD, decreased 51Cr release was associated with the presence of plasma factor(s) inhibiting phytohemagglutinin (PHA)-induced transformation of normal lymphocytes. Lymphocytes from approximately 50% of the patients with PBC exhibited cytotoxicity for hepatic cells but 25% showed less 51Cr release than controls and the remaining patients had results in the normal range. Lymphocyte cytotoxicity was also greater during the earlier stage of PBC. In contrast to CALD, decreased 51Cr release was not associated with the presence of plasma factor(s) inhibiting PHA-induced transformation of normal lymphocytes. Our findings support the hypothesis of in vivo lymphocyte-mediated liver cell damage in CALD and PBC, suggesting a potentially important role for lymphocyte suppression in the pathogenesis of both diseases.