Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.

BACKGROUND: Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice. AIM: To investigate whether clinical complications of cirrhosis may define different prognostic disease stages. METHODS: Analysis of the database from a prospective inception cohort of 494 patients. Decompensation was defined by ascites, bleeding, jaundice or encephalopathy. Explored potential prognostic stages: 1, compensated cirrhosis without oesophago-gastric varices; 2, compensated cirrhosis with varices; 3, bleeding without other complications; 4, first nonbleeding decompensation; 5, any second decompensating event. Patient flow across stages was assessed by a competing risks analysis. RESULTS: Major patient characteristics were: 199 females, 295 males, 404 HCV+, 377 compensated, 117 decompensated cirrhosis. The mean follow-up was 145 ± 109 months without dropouts. Major events: 380 deaths, 326 oesophago-gastric varices, 283 ascites, 158 bleeding, 146 encephalopathy, 113 jaundice, 126 hepatocellular carcinoma and 19 liver transplantation. Patients entering each prognostic stage along the disease course were: 202, stage 1; 216, stage 2; 75 stage 3; 206 stage 4; 213 stage 5. Five-year transition rate towards a different stage, for stages 1-4 was 34.5%, 42%, 65% and 78%, respectively (P < 0.0001); 5-year mortality for stages 1-5 was 1.5%, 10%, 20%, 30% and 88% respectively (P < 0.0001). An exploratory analysis showed that this patient stratification may configure a prognostic system independent of the Child-Pugh score, Model for End Stage Liver Disease and comorbidity. CONCLUSION: The development of oesophago-gastric varices and decompensating events in cirrhosis identify five prognostic stages with significantly increasing mortality risks.

Octreotide compared with placebo in a treatment strategy for early rebleeding in cirrhosis. A double blind, randomized pragmatic trial.

beta-Blockers and sclerotherapy prevent long-term upper digestive rebleeding in cirrhosis but they seem ineffective for early rebleeding. We compared octreotide with a placebo for the prevention of early rebleeding in cirrhotic patients. After control of acute upper digestive bleeding, 262 consecutive cirrhotic patients were randomized to octreotide 100 microgram subcutaneously three times a day for 15 days (n = 131) or to the placebo (n = 131), in a double blind pragmatic trial in which beta-blockers and/or sclerotherapy were allowed together with the experimental treatment. Separate randomization and analysis were performed according to whether patients were eligible for beta-blockers and/or sclerotherapy (101 placebo, 97 octreotide) or not (30 placebo, 34 octreotide). Rebleeding within 15 days was the primary measure of treatment efficacy; 6-week rebleeding rate was also assessed as a secondary measure. Fifteen-day cumulative proportions of patients rebleeding were 28% in the placebo group and 24% in the octreotide group (P = .40); corresponding figures among the 198 patients eligible to beta-blockers and/or sclerotherapy were 26% and 16% (P = .05) and among the 64 not eligible for these treatments 33% and 49% (P = .29). Among patients eligible to beta-blockers and/or sclerotherapy, a significant reduction of rebleeding episodes (35 vs. 18, P = .03), blood transfusions (75 vs. 50, P = .04), and days of stay in hospital (1,544 vs. 1,190, P = .0001) was also found in the octreotide group: this beneficial effect was confirmed 6 weeks after randomization. Mortality was not affected by octreotide in either group of patients. It is suggested that octreotide may reduce the risk of early rebleeding in cirrhotic patients treated with beta-blockers and/or sclerotherapy after control of acute upper digestive bleeding. Further studies are needed to confirm this result.

Fulminant hepatic failure in adult onset Still's disease.

Adult onset Still's disease (AOSD) is a well characterized rheumatoid disorder with frequent liver involvement. This is usually asymptomatic but severe hepatic failure has occasionally been reported. We describe a 44-year-old woman who developed acute liver failure 2 months after presenting symptoms of AOSD. Full etiologic evaluation was done and all other causes of liver failure were excluded. She underwent emergency orthotopic liver transplantation but developed disseminated intravascular coagulation with acute renal failure, seizures, and coma, and died after 48 hours.

Expression of leukocyte adhesion molecules in the liver of patients with chronic hepatitis B virus infection.

Virus-specific T-cell responses are believed to be involved in the pathogenesis of liver cell injury secondary to hepatitis B virus infection. In this study, liver biopsy specimens from patients with chronic hepatitis B virus infection were analyzed for expression of two major pathways of adhesion used by cytotoxic T cells to interact with target cells. The lymphocyte function-associated antigen 3 was found preferentially expressed on hepatocytes of patients with active hepatitis B virus replication, whereas the expression of the intercellular adhesion molecule 1 on hepatocytes seemed more closely related with inflammatory activity. Adhesion molecules were also highly expressed on T lymphocytes found in areas of piecemeal and spotty necrosis, indicating the presence of antigen-specific "memory" T cells at the site of hepatocellular injury. This study suggests that the expression of the lymphocyte function-associated antigen 3 on hepatocytes may be important for viral elimination. The coordinate expression of the intercellular adhesion molecule 1 may regulate inflammatory response and enhance viral antigen presentation to T cells. Conversely, the absence of hepatocyte adhesion molecules might be a favorable factor for viral persistence.

Procollagen type I production by hepatocytes: a marker of progressive liver disease?

The presence of collagen-producing cells and its relation to disease activity were determined in cryostat liver tissue sections from subjects with active cirrhosis (n = 15), inactive cirrhosis (n = 5), chronic persistent hepatitis (n = 8), or normal histology (n = 3) by means of an immunofluorescence technique using a monoclonal antibody to the carboxy-terminal domain of procollagen type I (anti-Pc). In all patients with active cirrhosis hepatocytes showed a strong intracellular staining with anti-Pc; in 4 of them bileducts also showed a membrane-like reaction. By contrast, tissue sections from chronic inactive liver disease and normal liver were essentially negative. These findings suggest that in chronic liver disease hepatocytes and sometimes biliary epithelium produce collagen and that production is related to disease activity. The detection of active production of procollagen type I by hepatocytes could become a useful marker of progressive liver disease.

Delta agent infection in acute hepatitis and chronic HBsAg carriers with and without liver disease.

Hepatitis B virus (HBV) is a major cause of chronic liver disease in southern Italy. In the same area superinfection with the delta agent is endemic. To assess the prevalence of delta infection in a large population of patients with acute and chronic HBV related liver disease and to look for differential features among delta infected and uninfected subjects sera from 592 consecutive HBsAg positive patients were tested for the delta/anti-delta system by RIA. In no case was delta Ag found in serum. The prevalence of anti-delta was low in acute hepatitis (6.6%) and in asymptomatic carriers (6.4%) but raised in chronic active hepatitis with or without cirrhosis (52.3%). A decrease in frequency of anti-delta was seen in inactive cirrhosis (38.8%) and in hepatocellular carcinoma (11.9%). A younger mean age of delta-infected subjects was observed in each type of chronic liver disease. Our data confirm that delta agent superinfection is definitely associated with severe chronic active liver disease. The difference in age between anti-delta positive and negative patients suggests that delta infection accelerates the natural history of HBV related liver disease.

Tissue markers of hepatitis B virus infection in hepatocellular carcinoma and cirrhosis.

In order to assess the prevalence of tissue markers of HBV infections (HBsAg and HBcAg) in HBsAg seropositive and seronegative hepatocellular carcinoma (HCC) as compared with other advanced liver diseases (inactive cirrhosis, IC, and active cirrhosis, AC), we studied 49 patients with HCC (13 HBsAg+), 52 patients with IC (5 HBsAg+) and 53 patients with AC (14 HBsAg+). Among HBsAg seropositive patients, intrahepatic HBsAg was frequently found (26/32 cases), while HBcAg was present more rarely (5/32 cases) and correlated with serological features of high-level viral replication. HBsAg seronegative, anti-HBc +/- anti-HBs positive subjects had intrahepatic HBsAg in 8/34 cases, and HBcAg in liver cell nuclei in 14/34 cases. HBcAg was more frequent in cirrhosis than in HCC. No other differences in the intrahepatic display of HBV markers was observed, nor was a specific pattern identified for HCC. Viral components were never found in the liver in the absence of serum HBsAg or anti-HBc. Neoplastic hepatocytes did not usually support the synthesis of HBsAg or HBcAg.

[Glycosylated hemoglobins and erythrocyte 2,3-diphosphoglycerate in diabetes mellitus]. / Emoglobine glicosilate e 2,3 difosfoglicerato eritrocitario nel diabete mellito.

Investigations carried out on 43 diabetic not ketoacidotic patients (32 women and 11 men) showed that the percentage of glycosylated hemoglobins (GHb) is significantly (p less than 0.01) inversely related to the intra-erythrocytic concentration of 2,3-DPG and to the calculated P50. Preliminary data from a prospective study suggest that the inverse relationship could be referred to the degree of control of the disease. In poorly controlled diabetes, where at the highest percentages of GHb the lowest levels of 2,3-DPG are found, less oxigen can be delivered to peripheral tissues.

[Behavior of plasma triglycerides and cholesterol in diabetic patients]. / Comportamento dei trigliceridi e del colesterolo plasmatici in pazienti diabetici.

34 diabetic patients (24 females and 10 males) were studied and hypertriglyceridemia was found only in females. Obesity seems to be the most important factor determining hypertriglyceridemia and hypercholesterolemia. No correlation was found between glycosylated haemoglobin and triglycerides or cholesterol levels. Only a little correlation was found between fasting plasma glucose and triglycerides levels.