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Biomedical subjects

R G Knodell

Publications and source records attributed to R G Knodell.

At least 19 recordsLinked to original sources
PubMed1992

Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group.

BACKGROUND: Acute non-A, non-B hepatitis after blood transfusion often progresses to chronic hepatitis and sometimes culminates in cirrhosis or even hepatocellular carcinoma. However, the frequency of these sequelae and their effects on mortality are not known. METHODS: We traced patients with transfusion-related non-A, non-B hepatitis who had been identified in five major prospective studies conducted in the United States between 1967 and 1980. We matched each patient with two control subjects (identified as the first and second controls) who received transfusions but who did not have hepatitis. The mortality rates in the three groups were determined with use of data from the National Death Index and Social Security Death Tapes. Cause-specific mortality was determined by reviewing death certificates. RESULTS: Vital status was established for over 94 percent of the 568 patients who had had non-A, non-B hepatitis and the two control groups (526 first controls and 458 second controls). After an average follow-up of 18 years, the estimate by life-table analysis of mortality from all causes was 51 percent for those with transfusion-associated non-A, non-B hepatitis, as compared with 52 percent for the first controls and 50 percent for the second controls. The survival curves for the three groups were virtually the same. Mortality related to liver disease was 3.3, 1.1, and 2.0 percent, respectively, among the three groups (P = 0.033 for the comparison of the group with non-A, non-B hepatitis with the combined control group). Seventy-one percent of the deaths related to liver disease occurred among patients with chronic alcoholism. CONCLUSIONS: In this long-term follow-up study, there was no increase in mortality from all causes after transfusion-associated non-A, non-B hepatitis, although there was a small but statistically significant increase in the number of deaths related to liver disease.

Alcoholism↗
PubMed1991

Differential inhibition of individual human liver cytochromes P-450 by cimetidine.

Cimetidine binds to cytochrome P-450 and inhibits hepatic metabolism of various drugs in humans. However, cytochrome P-450 is a family of enzymes rather than a single protein, and effects of cimetidine on individual human liver cytochromes P-450 have not been previously characterized. Metabolism of selected substrates and cimetidine-binding assays have been performed using human liver microsomes, purified human liver cytochromes P-450, and cytochrome P-450 complementary DNA-expressed yeast proteins to probe interaction of cimetidine with these individual enzymes. Cimetidine (3.0 mmol/L) in incubations reduced bufuralol hydroxylase activity by 80% and strongly inhibited microsomal nifedipine oxidation (23% +/- 13% of control activity). The same concentration of cimetidine produced intermediate inhibition of cytochrome enzymes responsible for ethoxyresorufin deethylation and aniline hydroxylation (77% +/- 6% and 68% +/- 17% of activity in control microsomal incubations, respectively), but little effect on tolbutamide hydroxylation was observed. Concordantly, the calculated binding constant for the binding of cimetidine to a purified cytochrome P-450 with high tolbutamide hydroxylase activity was 4.4 mmol/L, whereas the calculated binding concentration constant for a purified cytochrome P-450-metabolizing nifedipine was 0.7 mmol/L. These studies show a high variability in the effect of cimetidine on drug metabolism by individual human liver cytochromes P-450. In vitro studies using human liver microsomes and genetically engineered human cytochromes P-450 can be very useful in exploring important clinical questions of hepatic drug metabolism.

Adult↗
PubMed1991

Nodular regenerative hyperplasia: a cause of ascites and hepatomegaly after chemotherapy for leukemia.

Tender hepatomegaly and ascites occurred in a young woman receiving cytosine arabinoside and daunorubicin for acute myelogenous leukemia. Whereas veno-occlusive disease was suspected clinically, liver biopsy showed nodular regenerative hyperplasia with no evidence of hepatic vein abnormalities. It is postulated that nodular regenerative hyperplasia can be initiated by hepatotoxicity of chemotherapy agents used to treat leukemia and/or that these agents exacerbate clinical manifestations of this histological abnormality. Nodular regenerative hyperplasia should be added to the list of liver problems occurring in patients with leukemia.

Abdominal Pain↗
PubMed1990

Influence of hyperalimentation on rat hepatic microsomal fluidity and function.

Total parenteral nutrition with an amino acid-glucose solution has previously been shown to decrease rat hepatic drug metabolism compared with drug metabolic activity observed in rats receiving the same solution enterally and chow-fed animals. Because changes in membrane fluidity and lipid composition are reported to influence activity of a number of liver enzymes, effects of parenteral and enteral nutrition on hepatic microsomal membrane fluidity and lipid composition were assessed and compared with hepatic mixed-function oxidase activity. Both parenteral and enteral hyperalimentation produced a significant decrease in microsomal membrane fluidity (fluorescence anisotropy = 0.155 +/- 0.003 in both experimental groups versus 0.129 +/- 0.003 for microsomes from chow-fed animals). However, meperidine demethylase activity was significantly decreased compared with chow-fed experiments only in hepatic microsomes from parenterally hyperalimented animals, whereas ethoxyresorufin deethylase activity was significantly reduced only in the enteral-nutrition group. Inclusion of lipid in the parenterally administered hyperalimentation solution normalized microsomal membrane fluidity and lipid profile to those of chow-fed animals but did not increase hepatic meperidine demethylation. Both parenteral and enteral nutrition produce significant changes in physical state and lipid composition of rat hepatic microsomal membranes, but these changes are not responsible for the altered hepatic drug metabolism observed during hyperalimentation.

Animals↗
PubMed1977

Development of chronic liver disease after acute non-A, non-B post-transfusion hepatitis. Role of gamma-globulin prophylaxis in its prevention.

Progression of acute type B hepatitis to chronic liver disease and cirrhosis is well recognized, whereas no progression of acute type A hepatitis has as yet been documented. The natural history of acute non-A, non-B hepatitis has not been previously characterized. Ten cases of chronic liver disease were identified in 44 cases of acute non-A, non-B post-transfusion hepatitis. Age, sex, severity of acute illness, and prevalence of preoperative antibodies to known hepatitis-producing agents did not differ between the group whose hepatitis progressed to chronicity and the group whose hepatitis resolved. Less progression of acute hepatitis to chronic liver disease was seen in those patients receiving immune serum globulin preoperatively than in those receiving an albumin placebo (P = 0.009). Only 3 patients had clinical symptoms of hepatitis at the time of liver biopsy, and elevations of liver enzymes and gamma-globulin were mild. However, liver biopsy specimens in 8 of 10 patients showed chronic active hepatitis and an additional biopsy specimen showed cirrhosis. Acute non-A, non-B post-transfusion hepatitis often progresses to chronic active hepatitis. Preoperative gamma-globulin prophylaxis significantly reduces this progression. Identification and characterization of this viral agent(s) will further aid in the prevention of this undesirable complication of blood transfusion.

Acute Disease↗
PubMed1976

Efficacy of prophylactic gamma-globulin in preventing non-A, non-B post-transfusion hepatitis.

Of 279 cardiac-surgery patients receiving a mean of twelve transfusions, 47 had significantly increased transaminase concentrations 14 to 180 days postoperatively and 10 were icteric. Preoperatively, each patient randomly received high-titre HbsAb gamma-globulin, normal gamma-globulin, or placebo and was followed at intervals for 9 months. Only 3 patients had serological evidence of hepatitis-B infection. 3 additional patients had serological evidence of cytomegalovirus infection, while none had evidence of hepatitis-A or Epstein-Barr infection. Less icteric hepatitis occurred in patients receiving the gamma-globulin preparations (P = 0-003), and the overall frequency of hepatitis was significantly reduced when compared with recipients of placebo. The protective effects of the two gamma-globulin preparations were not significantly different. Most post-transfusion hepatitis tody is neither viral hepatitis type B nor type A, and its severity and transmission are reduced by pre-transfusion gamma-globulin.

Adult↗
PubMed1976

Effects of phototherapy on hepatic function in human alcoholic cirrhosis.

Phototherapy has been used to treat neonatal jaundice, but little assessment has been made of possible beneficial effects on adult liver disease. Effects of phototherapy on bile acid turnover, biliary lipid concentration, liver function tests, and bromosulfophthalein (BSP) kinetics were studied in 8 alcoholic cirrhotics. Phototherapy initially increased biliary specific activity of both primary bile acids and then produced an acceleration of cholic and chenodeoxycholic acid decay curves. Pruritus was relieved in the 3 patients who had this symptom. The proposed mechanism for these changes is mobilization of bile acids from an expanded cutaneous bile acid pool with augmented bile acid excretion. No significant change in serum liver function tests or BSP plasma disappearance curves was seen. Phototherapy causes little improvement in intrinsic liver function, but produces specific changes in bile acid metabolism; these changes may be related to effects of light on a cutaneous bile acid pool.

Adult↗
PubMed1976

Deoxycholate metabolism in alcoholic cirrhosis.

Deoxycholate is often absent in bile of patients with alcoholic cirrhosis. The purpose of this study was to define the mechanism for this abnormality in bile acid metabolism in alcoholic cirrhosis. Excretion and hepatic metabolism of exogenous [14C]deoxycholate were determined, quantitative and qualitative analyses of fecal bile acids were performed, and ability of fecal bacteria to metabolize cholate to deoxycholate in vitro was measured both in cirrhotic patients and in controls. There was no evidence for deoxycholate malabsorption or rehydroxylation. In cirrhotic patients without biliary deoxycholate, both in vivo levels of deoxycholate and lithocholate in feces and in vitro fecal bacterial conversion of cholate to deoxycholate were significantly decreased as compared to controls. The marked decrease in 7 alpha-dehydroxylase activity of fecal bacteria of some patients with alcoholic cirrhosis results in impaired conversion of cholate to deoxycholate and explains the lack of biliary deoxycholate in these patients.

Adult↗
PubMed1976

Effect of phototherapy on bilirubin excretion in man and the rat.

Further evidence that the bilirubin excreted by Gunn rats during phototherapy is unconjugated is presented. The unconjugated bilirubin is not carried into bile as a water-soluble complex with rapidly excreted bilirubin derivatives, nor as a result of leakage of plasma protein into bile. Phototherapy does not augment biliary excretion of bilirubin in normal nonjaundiced rats, but does increase the concentration of conjugated bilirubin in the bile of patients with alcoholic cirrhosis, although their serum bilirubin concentrations are unaffected. The mechanism for augmented excretion of unconjugated bilirubin during phototherapy remains unexplained.

Alcoholism↗
PubMed1975

Effects of chlorpromazine on bilirubin metabolism and biliary secretion in the rat.

Chlorpromazine (CPZ) is a long recognized cause of jaundice, but the mechanism by which this agent produces icteric liver disease is not well defined. This study examined some effects of CPZ administration on bilirubin metabolism and biliary secretion in the rat. Acute CPZ treatment (25 mg per kg intravenously) produced hemolysis and resulted in increased bilirubin output and stimulation of hepatic heme synthesis. Both unconjugated bilirubin and a gamma-azopigment found primarily in obstructed rat bile were seen. Acute infusion of hemoglobin solutions to simulate the hemolysis produced by acute CPZ treatment resulted in increased bilirubin output and increased hepatic heme synthesis, but no alterations in the normal conjugation pattern of bilirubin in bile were seen. Chronic CPZ treatment for 4 and 8 days (25 mg per kg intraperitoneally) increased bilirubin output without elevating plasma hemoglobin levels and increased the fraction of monoconjugated bilirubin in bile; the 8-day chronic treatment regimen also caused unconjugated bilirubin to appear in bile. No change in liver weight, bile salt, phospholipid, or cholesterol output was seen with chronic CPZ therapy. Changes in bilirubin production and conjugation caused by CPZ may be a contributing factor in this agent's hepatotoxicity.

Animals↗
PubMed1975

Etiological spectrum of post-transfusion hepatitis.

Frequent occurrence of post-transfusion hepatitis continues despite screening for Australia antigen in blood before transfusion and elimination of commercial donor sources. The majority of these cases appears unrelated to hepatitis B virus. Preoperative, acute, and convalescent serra were screened for evidence of hepatitis B, hepatitis A, Epstein-Barr, and cytomegalovirus exposure in 34 cardiac surgery patients developing post-transfusion hepatitis postoperatively. Four patients showed evidence of hepatitis B infection and 3 patients developed significant antibody titer rises to cytomegalovirus. No patient showed evidence for acute hepatitis A infection postoperatively in response to blood transfusions. Epstein-Barr virus was also not responsible for any cases of post-transfusion hepatitis. Presently available laboratory methods failed to implicate hepatitis A, Epstein-Barr, or cytomegalo-virus in the majority of non-B post-transfusion hepatitis cases. This suggests that identification and characterization of additional hepatitis-producing agents will be required to define further the epidemiology of post-transfusion hepatitis and develop measures for its prevention.

Antibodies, Viral↗
PubMedDate not supplied

Risk factors in transmission of non-A, non-B posttransfusion hepatitis. The role of hepatitis B antibody in donor blood.

Risk of developing icteric hepatitis in a transfusion study involving cardiac surgery patients was 0.2 per cent per unit of blood transfused with the ratio of icteric to anicteric cases being 1:4. Risk of developing hepatitis was proportional to the number of units transfused: one to four units, 4 per cent; six to ten units, 8 per cent; 11 to 20 units, 19 per cent; greater than 21 units, 42 per cent. The prevalence of type B hepatitis was low (6 per cent), with the vast majority of patients being shown to have non-A non-B hepatitis. However, a greater incidence of hepatitis type B serologic events was observed among recipients of anti-HBs positive blood than those transfused only with units not containing antibody (p = 0.04. A significantly greater incidence of non-A, non-B hepatitis was observed among patients transfused with blood containing anti-HBs when compared with a group who received blood without antibody (p less than 0.01). Caution should be exercised in interpretation of this difference because patients transfused with blood containing anti-HBs received significantly more units of blood. However, utilization of stepwise regression analysis to unconfound the two dependent variables suggest that the use of blood containing anti-HBs increases the hepatitis risk (p = 0.06) although the number of units transfused was the more significant factor (p less than 0.001). Additional data from carefully designed studies are needed to determine if donor blood containing anti-HBs significantly increases the risk of transmitting non-A, non-B hepatitis.

Antibodies, Viral↗