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A liver biopsy material comprising 477 biopsies from 477 patients included in a prospective, unblinded, randomized trial of treatment of cirrhosis with prednisone has been re-evaluated using new and more restrictive histological criteria for the diagnosis of cirrhosis and chronic aggressive hepatitis (CAH). The material was divided according to the likelihood of cirrhosis being present: (A) cirrhosis (287 patients), (B) probably cirrhosis (101 patients) and (C) compatible with but not diagnostic for cirrhosis (89 patients). Each group was further divided according to the presence (I) or absence (II) of CAH. A total of 98 patients fulfilled the histological criteria for CAH. The effect of prednisone concerning survival was evaluated in each group. In the total group of patients with CAH a significant beneficial effect of prednisone was found (p = 0.04). Among these patients the subgroup with cirrhosis in addition (group I A) also showed a significant effect of prednisone, while groups I B and I C only had a trend towards a beneficial effect (p = 0.44 and p = 0.36, respectively). In patients without CAH in the biopsy (Group II, A + B + C), no effect of prednisone was seen although a trend towards a harmful effect was found in patients with cirrhosis (Group II A). Control patients with CAH in all three subgroups had an insignificantly shorter survival than patients without CAH. All the CAH groups significantly more often included female patients with no history of alcoholism and a lower frequency of spider naevi. In addition, the CAH groups were more active as judged by biochemical and histological variables. It was further disclosed that the presence of large piecemeal necroses indicated a favourable effect of prednisone treatment, while alcoholism, ascites and male sex acted as indicators for an unfavourable treatment effect.

The natural history of gastrointestinal bleeding in cirrhosis has been studied using prospectively collected data of 532 patients included in a randomized clinical trial with a regular follow-up of up to 12 yr. Of the total 199 patients who experienced gastrointestinal bleeding, 95 (48%) bled from esophageal or gastric varices, 67 (34%) bled from peptic ulcer or gastritis, and 37 (18%) had either insufficient evidence of the source (33) or mixed sources (4). In the total group of patients the cumulative percentage of patients in whom varices had been demonstrated of patients in whom varices had been demonstrated by radiography increased from 12 to 90 in 10 yr, while that of bleeding from varices increased from 7 to 40. In 104 patients who bled for the first time during the trial period (trial bleeding patients) the median number of bleeding episodes was one (range 1-8). In these patients the fatality from bleeding from varices was 82%. The risk of rebleeding from varices was 81%, and 4 yr after the first bleeding the cumulative survival had decreased to less than 10%. Rebleeding was significantly less frequent and survival significantly higher in patients bleeding from sources other than varices. Prednisone reduced the occurrence rate of varices, bleeding from varices, and death from bleeding varices in nonalcoholic females without ascites, 40% of whom fulfilled the histologic criteria of chronic active hepatitis. Prednisone significantly increased the occurrence rate of varices inpatient with ascites and of bleeding from varices in alcoholic patients. Prednisone significantly increased the occurrence rate of peptic ulcer in males and in patients without chronic active hepatitis.

Our aim was to construct an index that accurately predicts the degree of benefit or harm that prednisone therapy holds for patients with liver cirrhosis. The admission and survival data of 488 patients with cirrhosis who participated in a controlled clinical trial of prednisone in a dosage of 10-15 mg daily (251 patients) versus placebo (237 patients) and who were observed for up to 12 yr were analyzed using Cox's multiple regression model. Four variables each provided significant therapeutic information: antinuclear factor (p = 0.02) and large piecemeal necroses (p = 0.02) were associated with a beneficial effect, whereas ascites (p = 0.0004) and large regenerative nodules (p = 0.0007) were associated with a harmful effect of prednisone. From these four variables a therapeutic index was constructed. For a given patient the therapeutic index is a measure of how big the effect will be if prednisone is given. The gain in survival time obtained by administering prednisone according to the therapeutic index was estimated to be 349 yr, mainly confined to 217 patients with a significant positive (121) or negative (96) therapeutic index. The therapeutic index may prove useful for the optimal administration of prednisone treatment in new patients with cirrhosis.

A prospective, unblinded, randomized trial of treatment of cirrhosis and chronic aggressive hepatitis (CAH) with prednisone included 484 patients who were divided using both the clinical criteria: non-alcoholic females without ascites, and the morphological criterion: presence of a liver biopsy showing CAH. A total of 164 patients (34%) satisfied the three clinical criteria and biopsies from 95 patients (20%) showed CAH. By a cross-tabulation method between the two sets of criteria, four groups were formed. Evaluation of the treatment effect by means of relative death rate showed that the clinical criteria identified both a group of patients with a beneficial effect of prednisone (p less than 0.05) and a group with a harmful effect of the treatment (p less than 0.05). Patients with CAH also had a significant beneficial treatment effect, but patients without CAH showed only an insignificantly harmful effect of treatment. Patients fulfilling both sets of criteria had a beneficial effect of prednisone (p less than 0.05) and patients lacking both sets had a significantly harmful treatment effect. A significantly better survival was found in patients satisfying the clinical criteria without CAH in the biopsy than in patients with CAH and not fulfilling the clinical criteria (p = 0.03). In both the groups of patients with disagreement between the two sets of criteria, a trend towards a beneficial effect of prednisone was found. It is concluded that the simple clinical criteria in comparison with the histological criteria identify a larger group of patients with a beneficial effect of treatment.

A multivariate Cox regression analysis with time-dependent variables has been performed on the data of 415 patients with cirrhosis included in a controlled clinical trial of 10-15 mg prednisone daily versus placebo. The analysis showed that a poor prognosis was associated with a low prothrombin index, marked ascites, GI bleeding, high age, high daily alcohol consumption, high bilirubin and alkaline phosphatase and low albumin values, little liver connective tissue inflammation, and poor nutritional status. Prothrombin index and ascites showed significant interaction with the treatment in such a manner that high prothrombin index and absence of ascites were associated with a beneficial effect of prednisone, whereas low prothrombin index and presence of ascites were associated with a harmful effect of prednisone treatment. The final model was validated in independent patients by comparing their actual survival with that predicted from the model, using a split-sample testing technique. The prognostic factors were combined with an index that can be used to update prognosis whenever changes occur in the clinical status of a patient during the course of the disease. The probability of surviving the next 3 or 6 months can be estimated from the prognostic index at any time during the course. The index may be of value for the correct timing of special therapeutic procedures such as liver transplantation.

The time change of laboratory variables in cirrhosis was studied by analysis of data from 488 patients with cirrhosis included in a controlled clinical trial of long-term prednisone vs. placebo. In the placebo group, a marked regression towards normal was seen within 3 months of entry into the trial (increase in serum albumin, acetylcholinesterase, cholesterol, hemoglobin and decrease in erythrocyte sedimentation rate). The subsequent course did not show a clear pattern, except for a slight increase in serum bilirubin and decrease in albumin. When studied in relation to the time of death in patients dying from a "hepatic" cause, marked increase in bilirubin and decrease in prothrombin index, albumin and cholesterol were seen in the year prior to death with little change before that time. In the prednisone group, a more marked decrease in bilirubin, SGOT, alkaline phosphatase, gamma-globulin, sulfobromophthalein retention, erythrocyte sedimentation rate and increase in leukocytes, prothrombin index and cholesterol were seen during the first 3 months. In relation to time of death from a "hepatic" cause, similar changes were seen as in the placebo group except that alkaline phosphatase increased and cholesterol did not decrease. A beneficial effect of prednisone on survival, as expressed by a previously developed therapeutic index, was associated with decrease in SGOT, alkaline phosphatase and gamma-globulin within the first 3 months. An increase in SGOT during prednisone seemed to be associated with harmful effects of therapy.