Poul Schlichting

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.

Effect of omeprazole and cimetidine on duodenal ulcer. A double-blind comparative trial.

We conducted a double-blind randomized study of 132 patients to determine whether the new, investigational proton-pump inhibitor, omeprazole (30 mg per day), would accelerate healing and pain relief, as compared with cimetidine (1 g per day), in patients with duodenal ulcer. After two weeks of treatment, which was completed by all patients, the healing rates were 73 per cent in the omeprazole group and 46 per cent in the cimetidine group (P less than 0.01). After four weeks of treatment, which was completed by 118 patients, the corresponding figures were 92 and 74 per cent (P less than 0.05). In the omeprazole group 55 per cent of the patients were free of pain after the first week, as compared with 40 per cent of those treated with cimetidine (P greater than 0.05). No major clinical or biochemical side effects of omeprazole or cimetidine were noted. A six-month follow-up study revealed no significant difference between the recurrence rates after omeprazole and after cimetidine treatment. In May 1984 clinical trials with omeprazole were temporarily suspended, since a study of long-term toxicity in rats had shown the development of gastric carcinoid tumors.

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.

Prevalence of hereditary haemochromatosis in late-onset type 1 diabetes mellitus: a retrospective study

BACKGROUND Although genotyping studies suggest that hereditary haemochromatosis is one of the most common genetic disorders in white people, it is still thought of as an uncommon disease. Our aim was to test the hypothesis that hereditary haemochromatosis is a disease often overlooked in patients with late-onset type 1 diabetes mellitus, a late manifestation of untreated iron overload. METHODS We did a retrospective study in which we genotyped for the C282Y and H63D mutations in the haemochromatosis gene in 716 unselected Danish patients who developed type 1 diabetes mellitus after age 30 years and 9174 controls from the general Danish population. We also screened for hereditary haemochromatosis by assessment of transferrin saturation. FINDINGS More patients with diabetes (n=9, relative frequency 1.26%, 95% CI 0.58-2.37) than controls (23, 0.25%, 0.16-0.38) were homozygous for C282Y (odds ratio 4.6, 2.0-10.1, p=0.0001). These patients had unrecognised signs of haemochromatosis. Transferrin saturation and ferritin concentrations ranged from 57% to 102% and 17 microg/L to 8125 microg/L, respectively. Frequency of compound heterozygosity (C282Y/H63D) did not differ between patients with diabetes (eight) and controls (131) (odds ratio 0.8, 95% CI 0.4-1.7). Positive and negative predictive values of transferrin saturation greater than 50%, in identification of C282Y homozygosity, were 0.26 and 1.00, respectively. A saturation of less than 50% therefore excluded C282Y homozygosity, whereas a saturation of more than 50% suggested C282Y homozygosity. INTERPRETATION Measurement of transferrin saturation followed by genetic testing could prevent liver and heart problems and improve life expectancy in patients with diabetes. Population screening before the onset of diabetes might improve the outlook of patients even further, but will be less cost effective.

The treatment effect of alpha interferon in chronic hepatitis B is independent of pre-treatment variables. Results based on individual patient data from 10 clinical controlled trials

Alpha interferon induces HBeAg seroconversion in about one third of treated patients and has become an established treatment of chronic hepatitis B. A number of smaller studies have suggested that response to treatment is more likely to occur in patients with higher levels of transaminases, with recent (adult) onset, a history of acute hepatitis, low levels of HBV DNA and in heterosexual males. The aim of this European co-operative study was to estimate the effect of alpha interferon more accurately and to evaluate the influence of host pre-treatment variables on the effect of interferon. Individual data were collected from 751 patients from 10 controlled clinical trials on alpha interferon (lymphoblastoid or recombinant) treatment for chronic hepatitis B. Alpha interferon was administered to 496 patients, while 255 were untreated controls. Individual patient data were analysed by survival analysis (log rank test and Cox regression analysis), stratified by trial, with the disappearance of HBeAg as the major endpoint. The results showed that the HBeAg disappearance rate with or without interferon treatment was higher in patients with high aminotransferase levels, with a history of acute hepatitis and in male heterosexual patients disregarding HIV status. If HIV-positive patients were excluded, the effect of sexual orientation was not significant. Therapy with alpha interferon increased the a priori HBeAg disappearance rate by a factor of 1.76; the relative treatment effect of alpha interferon was independent of the tested pretreatment host variables, but dependent on the total (intended) interferon dose (low dose < or = 200 MU/m2 increased HBeAg disappearance by a factor 1.37; medium/high dose > or = 200 MU/m2 increased HBeAg disappearance by a factor 2.05). In conclusion, this meta-analysis suggests that the effect of alpha interferon is less than previously assumed and independent of pretreatment host variables tested. It confirms the higher therapeutic benefit of a total dose exceeding 200 MU/m2 and of selection of patients based on disease activity and immune reactivity. Although all patient seem to have the same relative benefit, the absolute benefit of alpha interferon treatment seems to be greatest in patients with high transaminase levels and with a history of acute hepatitis.

Reproducibility of Liver Biopsy Diagnosis in Relation to the Size of the Specimen

For the purpose of evaluating the reproducibility of the chief diagnosis and several individual lesions in liver needle biopsies in relation to the size of the biopsy, we investigated without knowledge of clinical data 100 liver specimens in five sessions with an increasing amount of tissue made visible. The material consisted of routine liver biopsy specimens that were 25 mm or longer, comprising 50 with acute viral hepatitis (AVH), 10 with chronic aggressive hepatitis (CAH), 10 with micronodular cirrhosis, 10 with macronodular cirrhosis, 10 with steatosis, and 10 with other diagnoses. For the statistical analysis of the chief diagnoses, Friedmans two-way analysis of variance and Cochrans Q-test have been used. The predictive value of a lesion present and a lesion absent was used in evaluating the efficiency of the diagnoses of the individual lesions. The microscopic diagnosis of AVH was found to be safe even on biopsies only 5 mm long. Furthermore, the predictive value of both presence and absence of ...

An open-labeled, randomized study comparing systemic interferon-α-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis

OBJECTIVE:The aim of this study was to compare the treatment efficacies of subcutaneous interferon-α-2A (IFN-α-2A) injections versus prednisolone enemas in active left-sided ulcerative colitis in an open-labeled, randomized study.METHODS:Sixteen ulcerative colitis patients received IFN-α-2A subcutaneously (dosage: first wk, 9 MIU three times weekly [t.i.w.]; second wk, 6 MIU t.i.w.; wk 3–12, 3 MIU t.i.w.), and 16 received prednisolone enemas for 30 days (100 ml once daily, 0.25 mg of prednisolone/ml). The Powell-Tuck Index, Inflammatory Bowel Disease Questionnaire (IBDQ) score, and rectal histological activities were assessed before and after treatment. Thirteen patients in the IFN-α-2A group and all 16 in the prednisolone enema group completed the treatment.RESULTS:IFN-α-2A treatment showed significant improvements in the Powell-Tuck Index (p = 0.0002), IBDQ score (p = 0.002), and rectal histological activity scores (p = 0.02). In the enema group, significant improvements were found in the Powell-Tuck Index (p = 0.0009), whereas no significant improvements were detected in the IBDQ scores (p = 0.055) or rectal histological scores (p = 0.052). There were no differences between scores of the two groups either before or after treatment. Only moderate side effects from the IFN-α-2A treatment were seen during the first 2–4 wk of treatment.CONCLUSION:IFN-α-2A treatment resulted in significant depression of the disease activity as reflected by the Powell-Tuck Index, IBDQ score, and histological disease activity scoring. The preliminary trial thus suggests that IFN-α-2A may be effective in the treatment of active left-sided ulcerative colitis. Larger, randomized trials are, however, warranted to confirm this finding, owing to possible type II errors in group comparisons.

Liver biopsy in chronic aggressive hepatitis. Diagnostic reproducibility in relation to size of specimen.

For the purpose of evaluating the reproducibility of the main diagnosis in liver needle biopsies and estimating the size of the specimen for an acceptable accuracy, 100 liver specimens selected from the daily routine, all 25 mm or more in length, were investigated. The material consisted of specimens from 50 patients with chronic aggressive hepatitis (CAH; including 37 without and 13 with suspicion of cirrhosis), 6 with macronodular cirrhosis, 5 with micronodular cirrhosis, 10 with acute viral hepatitis (including 3 with suspicion of chronicity), 10 with primary biliary cirrhosis, 6 with chronic persistent hepatitis, and 13 with other diagnoses. The specimens were investigated without knowledge of clinical data in five sessions with an increasing amount of tissue made visible. The predictive value of a diagnosis present (diagnostic specificity) and a diagnosis absent (diagnostic sensitivity) was used in evaluating the efficiency of the diagnosis made on the visible part of the biopsy. For CAH (with and without suspicion of cirrhosis) the number of biopsies with the correct diagnosis increased significantly with increasing amounts of tissue visible (p less than 0.01), and the required length for an acceptable accuracy of CAH was 15 mm. The diagnostic sensitivity for CAH was very high (94%) with only 5 mm tissue available and constant through all sessions.

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.

Evaluation of Treatment Response in Active Crohn's disease by low-field magnetic resonance imaging

AbstractBackground: To evaluate low-field magnetic resonance imaging (MRI) in detecting therapeutic response in active Crohns disease during treatment with systemic steroids. Methods: Eight patients with active Crohns disease were examined before and during treatment with systemic steroids (1 mg/kg/day) using low-field MRI (0.1 T) in transverse and coronal planes before and after an intravenously administered bolus of gadodiamide. Five healthy persons were once examined in the same way. MRI images were evaluated without knowledge of diagnosis, treatment, or findings of endoscopy, conventional radiography, and surgery. Proximal and mid small bowel, terminal ileum, right-sided colon, transverse colon, and left-sided colon were evaluated separately. Results: Statistically significant differences were shown for both signal intensity on T2- (SIT2) and increment in signal intensity on T1-weighted images after contrast (%SIT1) when comparing diseased bowel segments with both nondiseased bowel segments (SIT2: p= 0.0001; %SIT1: p= 0.0009) and segments from the control group (SIT2: p < 0.00005; %SIT1: p < 0.00005). In 53 of 56 bowel segments evaluated (95%), agreement was found between findings by MRI, conventional radiography, endoscopy and/or surgery regarding disease extension. Extension was underestimated in two patients. All bowel segments in the control subjects were evaluated to be normal on MRI. Significant correlation was found between both SIT1 (p < 0.0025) and %SIT1 (p < 0.025) versus endoscopic activity gradings. During treatment, significant decrements of both SIT2 (p < 0.00005), %SIT1 (p= 0.002), and bowel wall thickness (p= 0.03) were found. Conclusions: Low-field MRI seems to be a promising noninvasive method in the evaluation of response regarding both disease extension and activity in Crohns disease during treatment with systemic steroids.