Lis Fauerholdt

Aspects of the Natural History of Gastrointestinal Bleeding in Cirrhosis and the Effect of Prednisone

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.

Updating Prognosis and Therapeutic Effect Evaluation in Cirrhosis with Cox's Multiple Regression Model for Time-Dependent Variables

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.

Main causes of death in cirrhosis.

The main causes of 436 deaths among 532 patients with cirrhosis followed up for up to 16 years constituted liver failure (24%), liver failure with gastrointestinal bleeding (13%), gastrointestinal bleeding (14%), primary liver cell carcinoma (4%), other liver-related causes (2%), infections (7%), cardiovascular diseases (22%), extrahepatic malignancies (9%), and other non-liver-related causes (5%). Totally, 57% died of liver-related causes. A high frequency of liver-related death was found among patients with a short observation time, high biochemical activity, pronounced change in liver architecture, ascites, and other signs of a poor prognosis at the time of diagnosis. The findings favoured the hypothesis that cirrhosis of the liver is a disease with an initial active and a subsequent inactive phase. Half of the patients were treated with prednisone, but this had no detectable influence on the distribution of causes of or on the frequency of single causes of death as infections or gastrointestinal bleeding. The group of patients responding favourably to prednisone treatment with regard to survival (non-alcoholic women without ascites) showed causes of death not different from those of the total material.