Histological Disease Activity Research Articles

The pathology of hepatitis C as a function of mode of transmission: Blood transfusion vs. intravenous drug use

We reviewed the clinical records of 140 consecutively evaluated patients with chronic hepatitis C infection. One hundred twenty-four patients (89%) contracted infection through blood transfusion or intravenous drug use. The liver biopsy specimens of 83 patients (43 blood transfusion cases and 40 intravenous drug abuse cases) were examined without knowledge of the mode of disease transmission. The mean histological activity index score was significantly higher in the blood transfusion group (10.2 ± 4.2) than in the intravenous drug use group (6.9 ± 4.5) (p = 0.001). The transfusion group had more periportal bridging necrosis (p = 0.0015) and fibrosis (p = 0.0016) than did the intravenous drug use group, whereas significant differences between lobular degeneration and portal inflammation were not achieved across the two groups. The distribution of final biopsy interpretations also differed significantly between the two groups (p < 0.001), with chronic active hepatitis more frequent in the transfusion group. Moreover, lymphoid aggregates and bile duct damage were more common in patients with chronic hepatitis due to blood transfusion. Multivariate analysis showed that the mode of viral transmission was the most powerful predictor of histological activity index score when tested against patient gender, duration of disease or age at biopsy. One year after completion of this study, 9 of 70 transfused patients and 1 of 54 intravenous drug users had died of liver disease or are awaiting liver transplantation at this writing (p = 0.03). We conclude that transfusion-acquired hepatitis C is associated with more aggressive histological inflammatory activity than hepatitis resulting from intravenous drug use. We postulate that the severity of the initial pathological lesion predicts histological disease activity. (HEPATOLOGY 1993;18:1338–1343.)

Association between Tumor Necrosis Factor-α and Disease Progression in Patients with Multiple Sclerosis

Cachectin, or tumor necrosis factor-alpha (TNF-alpha), is a principal mediator of the inflammatory response and may be important in the pathogenesis and progression of multiple sclerosis, an inflammatory disease of the central nervous system. In a 24-month prospective study, we used a sensitive enzyme-linked immunosorbent assay to determine levels of TNF-alpha in cerebrospinal fluid and serum in 32 patients with chronic progressive multiple sclerosis and in 20 with stable multiple sclerosis and 85 with other neurologic diseases. An attempt was made to relate TNF-alpha levels with the degree of disability of the patients with multiple sclerosis and with their neurologic deterioration during the 24 months of observation. High levels of TNF-alpha were found in the cerebrospinal fluid of 53 percent of the patients with chronic progressive multiple sclerosis and in none of those with stable multiple sclerosis (P less than 0.001). TNF-alpha was detected in the cerebrospinal fluid of 7 percent of the controls (P less than 0.01) with other neurologic disease. In patients with chronic progressive multiple sclerosis, mean TNF-alpha levels were significantly higher in the cerebrospinal fluid than in corresponding serum samples (52.41 vs. 11.88 U per milliliter; range, 2 to 178 vs. 2 to 39; P less than 0.001). In these patients, cerebrospinal fluid levels of TNF-alpha correlated with the degree of disability (r = 0.834, P less than 0.001) and the rate of neurologic deterioration (r = 0.741, P less than 0.001) before the start of the study. Cerebrospinal fluid levels also correlated with the increase in neurologic disability after 24 months of observation (r = 0.873, P less than 0.001). These data provide evidence of intrathecal synthesis of TNF-alpha in multiple sclerosis and suggest that the level of TNF-alpha in cerebrospinal fluid correlates with the severity and progression of the disease. Our results suggest that TNF-alpha may reflect histologic disease activity in multiple sclerosis and could be used to monitor outcomes or responses to therapy.

Hepatitis B virus replication modulates pathogenesis of hepatitis D virus in chronic hepatitis D

Hepatitis D virus and hepatitis B virus nucleic acids were detected by Northern and Southern blot hybridization in the sera and livers of 85 chronic carriers of HBsAg and anti-hepatitis D followed up for a mean of 10 yr. We identified three subsets of patients: 13 with hepatitis D virus and hepatitis B virus viremia, 53 with serum hepatitis D virus RNA, but without hepatitis B virus DNA and 19 negative for both nucleic acids. Genomic and subgenomic forms of hepatitis D virus RNA were detected only in patients with hepatitis D virus and hepatitis B virus viremia. Histological findings and disease activity at admission were comparable in the three groups of patients, but the outcome was significantly worse in patients with active replication of both viruses; two of them died of terminal liver failure and hepatocellular carcinoma developed in two; the remaining patients had an uneventful course. These results suggest that active hepatitis B virus replication represents an important previously unrecognized determinant of severe liver damage in patients with chronic hepatitis D virus infection. Since hepatitis B virus provides the means for hepatitis D virus secretion and release from infected cells, active hepatitis B virus multiplication favoring the spread of hepatitis D virus from cell to cell may increase the pathogenetic potential of the defective agent.

Distribution of HBcAg in hepatitis B detected by immunoperoxidase staining with three different preparations of anti-HBc antibodies.

To evaluate the role of the expression of hepatitis B core antigen (HBcAg) in liver cell damage the immunoperoxidase staining pattern of cryostat liver biopsy specimens from 16 chronic carriers of hepatitis B surface antigen (HBsAg) was investigated using three different kinds of anti-HBc antibodies. Polyclonal antibody prepared from recombinant HBcAg seemed to be more sensitive in detecting HBcAg than did monoclonal antibody from the same antigen. The topographical distribution of HBcAg detected by these two antibodies was similar, showing a close correlation to the histological activity of disease. Furthermore, the predominant localisation of cytoplasmic HBcAg usually reflected an active and severe ongoing hepatitis. On the other hand, monoclonal antibody prepared from purified Dane particles resulted in the prominent cytoplasmic staining for HBcAg regardless of histological severity of the hepatitis. The quantitative expression and topographical distribution of HBcAg depended on the type of anti-HBc antibodies used.

Effects of topical 5-aminosalicylic acid and prednisolone on prostaglandin E2 and leukotriene B4 levels determined by equilibrium in vivo dialysis of rectum in relapsing ulcerative colitis

To determine the influence of inflammation and topical treatment with 5-aminosalicylic acid or prednisolone on arachidonic acid metabolism in vivo, we carried out a double-blind controlled study on the release of prostaglandin E2 and leukotriene B4 to the rectal lumen in 24 consecutive patients with proven distally located ulcerative colitis. Before and at days 15 and 29 a dialysis bag was placed in the emptied rectum for 4 h prior to assessing clinical, endoscopic, and histologic disease activity. A single enema was given daily at bedtime (1 g 5-aminosalicylic acid or 25 mg prednisolone) until complete remission or for a maximum of 4 wk. Clinical and endoscopic remission was obtained in 16 (7 on 5-aminosalicylic acid) and 11 (3 on 5-aminosalicylic acid) patients, respectively. Luminal concentrations of prostaglandin E2 and leukotriene B4 were positively correlated to disease activity and significantly decreased among the prednisolone-treated patients. In both treatment groups a decrease toward normal levels occurred in patients responding to therapy, in retrospect, the pretreatment prostaglandin E2 and leukotriene B4 levels were significantly higher in patients not responding to therapy than in those improving during treatment. In conclusion, luminal prostaglandin E2 and leukotriene B4 levels may prove more useful predictors of the outcome of treatment in relapsing ulcerative colitis than clinical indices of disease activity.

Lymphocyte cytotoxicity in chronic active hepatitis: effect of therapy and correlations with clinical and histological changes.

A study of lymphocyte cytotoxicity for rabbit hepatocyte cultures in 15 patients with untreated chronic active hepatitis showed positive results in all cases, both HBsAg positive and negative. After immunosuppressive therapy cytotoxicity became negative and remained negative, in four of nine patients followed serially. In 51 patients established on therapy for periods from three months to 12 years, cytotoxicity was negative in 19 and all patients are currently alive. However, in the remaining 32 patients in whom cytotoxicity was positive there has been a 34% mortality. Cytotoxicity remained persistently positive in 12 of 15 patients followed serially, and persistently negative in seven of nine. Cytotoxicity showed a significant association with histological disease activity, especially the extent of piecemeal necrosis, but not with biochemical tests of liver function, immunoglobulins, or autoantibodies. The basis of this cytotoxicity test is an antibody dependent cell-mediated autoimmune reaction directed against a liver specific protein, and the results suggest that in some cases immunosuppressive therapy is followed by control of this reaction. It may be possible to stop therapy in these patients, but in those in whom the reaction continues, as shown by continuing cytotoxicity, the prognosis is not as good and the use of other drug schedules would seem worthy of trial.