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Biomedical subjects

W C Maddrey

Publications and source records attributed to W C Maddrey.

At least 19 recordsLinked to original sources
PubMed1992

Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice.

BACKGROUND: Iron is essential for the growth of all living cells. One of the important intracellular roles for iron is in the activation of ribonucleotide reductase, the enzyme that catalyzes the first step in DNA synthesis. Thus, the intracellular iron level may serve as a regulator of cell growth. The authors tested the hypothesis that lowering body iron concentration inhibits the growth of human-derived hepatocellular carcinoma (HCC) cells by depleting these cells of iron. Deferoxamine (DFO), an iron-chelating agent, was used to lower intracellular iron level. METHODS: HCC cells, PLC/PRF/5 (7 x 10(6) cells/mouse), were transplanted subcutaneously into athymic nude mice. When tumors reached 200-300 microliters in size, mice with comparable tumor sizes were paired; one was treated with DFO (300 mg/kg body weight/day, 5 days/week) intraperitoneally while the other received no treatment. RESULTS: Eight pairs of mice with HCC were observed for 5-18 weeks. Mean tumor growth rates (TGR) (mean +/- standard error) for the untreated and treated mice were 30.5 +/- 3.7 microliters/week and 11.9 +/- 1.5 microliters/week. The difference was significant (P < 0.02). In the second set of studies, DFO treatment was begun when the tumor size was smaller (100-200 microliters). Four pairs of mice were observed for 4-15 weeks; mean TGR for the four untreated mice was 18.1 +/- 5.1 microliters/week. In two mice treated with DFO, tumors regressed completely by the seventh week after initiation of treatment. The two remaining mice on DFO therapy had much slower growing tumors, with a mean TGR of 1.8 +/- 0.5 microliters/week. CONCLUSIONS: Thus, our results suggest that (1) reduction of intracellular iron concentration by DFO may be useful as antitumor therapy in HCC and (2) the favorable effects of DFO treatment are best seen when treatment is begun when the tumor is small.

Animals↗
PubMed1992

Perspective: preventive isoniazid therapy and the liver.

The preventive use of isoniazid (INH) has been controversial since 1975, but official agencies continue to advocate the procedure. Cost-effectiveness and risk benefit studies of preventive INH use have come to conflicting conclusions. A review of eight such studies indicates an increasing tendency to minimize INH hepatotoxicity and to disregard the declining tuberculosis morbidity and mortality in countries in which INH prophylaxis has not been widely adopted. We report three cases of fatal INH-associated hepatitis that illustrate that this complication of preventive INH use remains a serious problem. Current recommendations that encourage wide use of preventive INH therapy are unwise because they inflict a risk of fatal hepatitis on compliant adults and older children who have little danger of tuberculosis while being difficult to deliver to the alcohol- and drug-addicted persons whose risk is high. Health departments and physicians should severely restrict preventive INH therapy.

Adolescent↗
PubMed1991

The serum concentrations of the aminoterminal propeptide of procollagen type III and the hepatic content of mRNA for the alpha 1 chain of procollagen type III in carbon tetrachloride-induced rat liver fibrogenesis.

Serum concentrations of the aminoterminal propeptide of procollagen type III (PIIIP) are elevated in fibrogenic diseases of the liver, but the mechanism of elevation is not fully understood. To investigate the mechanism, we compared serum concentrations of PIIIP with total liver content of mRNA for the pro alpha 1 (III) chain, in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. Adult male rats received CCl4 in mineral oil twice weekly for 8 weeks and were compared with age-matched controls. Serum concentrations of PIIIP were measured by a specific radioimmunoassay; molecular sizes of PIIIP in serum were also determined. Pro alpha 1 (III) mRNA content in the liver was quantitated by RNA slot-blot hybridization and chemical measurement of total hepatic RNA content. Total collagen content of the liver was estimated by hydroxyproline measurement. All CCl4-treated animals had septal fibrosis after 4 weeks, and evidence of cirrhosis (regenerative nodules, ascites) was seen after 7 weeks of treatment. Serum concentrations of PIIIP and pro alpha 1 (III) mRNA content in the liver were correlated well until cirrhosis has established. They increased simultaneously after 3 weeks of treatment, 1 week before any elevation of hepatic hydroxyproline could be detected. After cirrhosis has established, pro alpha 1 (III) mRNA content in the liver decreased markedly, but serum PIIIP levels continued to be elevated. Hepatic hydroxyproline plateaued after 5 weeks. The molecular sizes of serum PIIIP indicate the release of intact native procollagen peptide during the development of cirrhosis. In conclusion, at least in CCl4-induced liver fibrosis in the rats, serum PIIIP levels can be used as a fibrogenic marker for the period progressing to cirrhosis. But the use of the serum PIIIP levels in cirrhosis seems to be limited by factors other than liver fibrogenesis.

Actins↗
PubMed1991

Recurrence of hepatitis C virus infection after orthotopic liver transplantation.

Identification of the hepatitis C virus--the main cause of posttransfusion and sporadic non-A, non-B hepatitis--and the development of a diagnostic serological test have allowed us to study possible recurrence of this type of hepatitis after liver transplantation. Six of 34 consecutive transplant recipients were found to have had antibodies to hepatitis C before transplantation. All six patients had possible exposure to hepatitis C through blood transfusion or intravenous drug use. Five of the six patients were positive for antibodies to hepatitis C after 1 yr of follow-up. Two of these patients had clinical and histological evidence of acute viral hepatitis in their allografts. In one patient this led to hepatic injury and dysfunction of two successive grafts. In contrast, none of the twenty-eight patients who were seronegative for hepatitis C virus antibodies before transplantation has converted to seropositivity after transplantation despite perioperative blood transfusions. These results suggest that hepatitis C diagnosed serologically recurs in a minority of transplant recipients and that de novo seroconversion must be uncommon.

Adult↗
PubMed1991

Elevated intracranial pressure and computed tomography of the brain in fulminant hepatocellular failure.

Cerebral herniation is a leading cause of death in patients with fulminant hepatocellular failure. Classical signs of elevated intracranial pressure are often absent in these patients. A reliable noninvasive method by which the presence of cerebral edema could be determined is much needed. To assess the efficacy of computed tomography of the brain in this setting, we compared the radiographic findings to the intracranial pressure measured by an epidural monitor in patients with fulminant hepatic failure. Unfortunately, a considerable difference existed between the presence of cerebral edema diagnosed by computed tomography of the brain and elevation of the intracranial pressure. Our observations suggest that in patients with fulminant hepatic failure and advanced hepatic encephalopathy, computed tomography of the brain is of little value in detecting cerebral edema. Pressure monitoring is most important to establish the presence and guide the therapy of intracranial hypertension.

Brain↗
PubMed1990

Intrahepatic cholestasis and phospholipidosis associated with the use of trimethoprim-sulfamethoxazole.

Although liver injury after administration of the trimethoprim-sulfamethoxazole combination is rare, hepatocellular necrosis and cholestasis have developed in a few cases. We describe a patient who developed a severe, prolonged cholestatic reaction after trimethoprim-sulfamethoxazole administration. The findings from serial liver biopsy samples showed characteristic abnormalities of phospholipidosis that have not been previously described for trimethoprim-sulfamethoxazole-related hepatic injury. The most prominent finding on electron microscopic evaluation of the liver was the presence of prominent hepatocyte lysosomal inclusions characterized by concentric arrangements of membranous and lamellated structures. The patient improved after several courses of exchange plasmapheresis, which may have assisted in the removal of toxic drug-lipid complexes. The pathogenesis of this acquired secondary phospholipidosis is unknown. Possible mechanisms include generation of highly lipid-soluble metabolites and inhibition of the lysosomal enzyme phospholipase A1.

Chemical and Drug Induced Liver Injury↗
PubMed1990

Heterotopic liver transplantation for fulminant Wilson's disease.

Wilson's disease may present with severe acute hepatocellular failure. The only effective treatment for fulminant Wilson's disease is liver transplantation, which may lead to reversal of the underlying disease. Some patients with cirrhosis who are too ill to undergo orthotopic liver transplantation have been treated with heterotopic liver transplantation. However, use of heterotopic liver transplantation for fulminant hepatocellular failure has not been successful. This case study involves a patient in whom a heterotopic liver transplant was successfully used for treatment of Wilson's disease presenting with fulminant hepatocellular failure.

Adolescent↗
PubMed1990

Chromosomal rearrangements in a primary hepatocellular carcinoma.

Chromosome analysis of cells obtained at biopsy from a 65-year-old man with primary hepatocellular carcinoma revealed characteristic abnormalities of chromosomes 1, 5, 6, 9, 13, 16, and 22 in each cell and maintenance of a pseudodiploid chromosome number (46,XY). Five of the chromosomal sites involved in these rearrangements are either in fragile site regions or in regions containing genes that encode cellular oncogenes. Some of the tumor cells manifest mitotic deviations in the form of asynchronies, spiralization, premature centromere division, and non-sister chromatid associations. The significance of these findings to hepatocellular carcinogenesis is discussed.

Aged↗
PubMed1990

Raised histamine concentrations in chronic cholestatic liver disease.

Pruritus is a frequent symptom in chronic cholestatic liver disease. To date, no single causative mechanism has been identified. We examined venous plasma concentrations of the known pruritogen, histamine, using a highly sensitive radioenzymatic assay in 42 patients with chronic cholestatic liver disease, and in normal controls. The mean plasma histamine level was significantly greater in chronic cholestatic liver disease patients (275 (117) pg/ml; X (SD) than in controls (140 (72) pg/ml, n = 20) (p less than 0.0001). No significant differences were found between histamine concentrations in the two chronic cholestatic liver disease subgroups: primary biliary cirrhosis and sclerosing cholangitis. Histamine concentrations were significantly greater (p less than 0.01) in the pruritic (319 (132) pg/ml) as compared with the non-pruritic (227 (75) pg/ml) chronic cholestatic liver disease patients. The histaminase activity was equivalent in patients and controls. The finding of raised histamine concentrations in chronic cholestatic liver disease suggests in vivo mast cell activation and a potential role for its mediators in the pruritus characteristic of these disorders.

Adult↗
PubMed1990

Alcoholic hepatitis: pathogenesis and approaches to treatment.

Alcoholic hepatitis is a necrotizing, often inflammatory, process that is an important precursor to the development of cirrhosis. Acetaldehyde, which is derived from alcohol by the action of alcohol dehydrogenase, is apparently the most important factor leading to alcohol-induced liver injury. Other factors of importance in determining the appearance and rate of progression of liver diseases in patients who are chronic alcoholics include sex, nutritional status, and various immunologic reactions. In addition, there is an incompletely understood genetic predisposition to the development of alcoholic hepatitis. Several histologic features found in patients with alcoholic hepatitis have been evaluated in efforts to determine which are of prognostic value. The predominance of the alcohol-induced injury in zone III of the hepatic lobule; deposition of collagen, IgA, and fibronectin in the space of Disse; defenestration of endothelial cells; and transformation of lipocytes and myofibroblasts to fibroblasts have been investigated. Prolongation of the prothrombin time and marked elevation of serum bilirubin levels are indicators of a subgroup of patients with alcoholic hepatitis who have a poor prognosis, especially if there is also evidence of hepatic encephalopathy. Supportive care and abstinence from alcohol are the foundations of therapy. Corticosteroid therapy appears to decrease the number of early deaths in patients with severe alcoholic hepatitis. Other experimental approaches to therapy include the use of propylthiouracil, anabolic-androgenic steroids, and insulin and glucagon.

Acetaldehyde↗
PubMed1989

Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial.

STUDY OBJECTIVE: To determine the efficacy of a corticosteroid in reducing the short-term mortality of patients with severe alcoholic hepatitis. DESIGN: Randomized, double-blind, placebo-controlled multicenter trial. SETTING: Four university teaching hospitals. PATIENTS: We enrolled 66 patients with alcoholic hepatitis and either spontaneous hepatic encephalopathy or a discriminant function value greater than 32, calculated using the formula: 4.6 (prothrombin time - control time) + serum bilirubin [in mumol/L]/17.1. Fifty-nine patients (89%) completed the study. Two patients withdrew from the trial. The other 64 patients were hospitalized for the duration of the trial; however, treatment was discontinued in 5 patients because of potential drug toxicity. INTERVENTIONS: Patients were randomly assigned to receive either methylprednisolone (32 mg) or placebo within 7 days of admission. Treatment was given for 28 days. The doses were then tapered over 2 weeks and discontinued. MEASUREMENTS AND MAIN RESULTS: The endpoint of the study was death. Of the 31 recipients of placebo, 11 (35%) died within 28 days of randomization compared with 2 (6%) of the 35 patients given methylprednisolone (P = 0.006). The 95% CI for the difference in mortality was 12% to 70%. In the patients with spontaneous hepatic encephalopathy at entry, 9 of 19 recipients of placebo died (47%) compared with 1 (7%) of the 14 patients given methylprednisolone (P = 0.02). The 95% CI for the difference in mortality was 14% to 66%. The Cox proportional hazards regression model showed the advantage of methylprednisolone over placebo after adjustment for other potentially important prognostic variables (P = 0.004). CONCLUSIONS: Methylprednisolone therapy decreases short-term mortality in patients with severe alcoholic hepatitis manifested either by spontaneous hepatic encephalopathy or a markedly elevated discriminant function value.

Adult↗