Biomedical subjects
R E Kirsch
Publications and source records attributed to R E Kirsch.
Elevated fibrin-related and fibrinogen-related antigens in patients with liver disease.
Patients with liver disease have a variety of coagulation abnormalities. These derangements are of uncertain origin and do not always correlate with disease severity or activity. We have measured the levels and proportions of the total fibrin-related and fibrinogen-related antigens, the principal fibrin (D-dimer) and fibrinogen (D-monomer) degradation fragments and intermediates of fibrin formation (fibrin monomers) in patients with a variety of acute and chronic liver diseases in whom all known other precipitating causes of disseminated intravascular coagulation had been excluded. Fibrin-related and fibrinogen-related antigens were extracted from serum using antihuman fibrinogen-IgG covalently bound to activated amino-phenylthioether paper disks and were subjected to 4% to 11% sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. Fibrin-related and fibrinogen-related antigen proportions were determined by densitometry, and their levels were measured by radioimmunoassay. Levels of total fibrin-related and fibrinogen-related antigens (and D-dimer) were significantly elevated (p less than 0.01) in patients with cirrhosis (121 to 641 ng/ml) and hepatocellular carcinoma (416 to 8,786 ng/ml) when compared with patients with acute viral hepatitis (84 to 322 ng/ml) and control subjects (38 to 186 ng/ml). In addition, D-monomer levels were elevated. These findings strongly suggest that disseminated intravascular coagulation is a component of the coagulopathy of certain liver diseases. Because fibrin-related and fibrinogen-related antigens have anticoagulant, vasoactive and immunosuppressive properties, their elevated presence may be biologically significant in these patients.
Safety and efficacy of interferon alpha-2b following prednisone withdrawal in the treatment of chronic viral hepatitis B. A case-controlled, randomised study.
The therapeutic effects of interferon alpha-2b (Intron A; Scherag) in patients with chronic active hepatitis caused by hepatitis B virus (HBV) were assessed in a randomised, case-controlled clinical trial conducted between January 1988 and June 1990. Treatment involved a short course of prednisone followed by interferon alpha-2b, initially 10 million U by subcutaneous injection, 3 times a week for 16 weeks. All patients were symptomatic, were known to have had hepatitis B surface antigen and hepatitis B e antigen (HBeAg) in their blood for at least 6 months, and had elevated serum aminotransferase activities with histological evidence of chronic active hepatitis. Patients with carcinoma, renal or haematological abnormalities or decompensated cirrhosis were excluded. In 6 of 10 patients randomised to receive interferon and 1 of 10 controls, HBeAg and HBV DNA were cleared from the blood during the 12-month study period (P < 0.05). An indeterminate response with clearance of HBV DNA but persistence of HBeAg was noted in 1 patient receiving interferon. Serum aminotransferase levels decreased only in those patients who had responded to treatment, but this did not reach statistical significance for the group as a whole. Histological studies, where available, showed decreased hepatic periportal necrosis in patients who underwent treatment. Two patients relapsed to HBeAg-positive status 2 months after their initial seroconversion; 1 became clear again during a repeat course of interferon. Side-effects of treatment were common and included fever, malaise, myalgias and myelosuppression. One patient developed hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine, benzoylecgonine, ecgonine methyl ester, and norcocaine blood levels in pigs.
We measured the blood levels of cocaine and its three major metabolites, benzoylecgonine, ecgonine methyl ester, and norcocaine, in three groups of male pigs weighing about 26 kg (25.75 +/- 0.25 kg) to determine the effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine metabolism. In addition, systemic elimination half-life, volume of distribution, and clearance of cocaine were calculated for the three groups. Group 1 pigs (n = 4) were pretreated with normal saline solution, group 2 pigs (n = 4) were pretreated with tetraisopropyl pyrophosphoramide, a specific plasma cholinesterase inhibitor, and group 3 pigs (n = 4) were pretreated with cimetidine, a hepatic microsomal enzyme inhibitor, all administered intramuscularly. Pigs were anesthetized with intravenous sodium thiopental; a carotid arterial cannula and an external jugular catheter were then inserted for the administration of cocaine and for blood sampling. Forty-five minutes later, when pigs were again completely awake, cocaine 3 mg/kg was given intravenously. Arterial blood samples were collected for the analysis of cocaine and cocaine metabolite levels just before and at 5, 10, 15, 30, 45, 60, 120, 180, and 1440 minutes after the administration of cocaine. Cocaine and cocaine metabolite blood levels were analyzed with high-pressure liquid chromatography methods and plasma cholinesterase activity was measured with a colorimetric method. The blood levels of cocaine and cocaine metabolites were significantly different among the three groups (p less than 0.05, analysis of variance). Statistically significant differences in half-life, volume of distribution and clearance were also seen among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Orthotopic liver transplantation at Groote Schuur Hospital.
We present data on 10 patients (5 men and 5 women, aged 21-56 yrs) with end-stage liver disease or tumour who underwent orthotopic liver transplantation at Groote Schuur Hospital between October 1988 and June 1991. Standard surgical techniques were used for procuring the donor liver, the recipient hepatectomy and the implantation of the liver. The venovenous bypass method was used in all but 2 patients. Postoperative immunosuppression was usually achieved with cyclosporin, azathioprine and low-dose steroids. Six patients were treated with prophylactic OKT3. Rejection episodes were treated with bolus doses of intravenous steroids. The indications for liver transplantation included chronic active hepatitis progressing to cirrhosis (5), biliary cirrhosis in association with inflammatory bowel disease (1), sclerosing cholangitis (2), alpha 1-antitrypsin deficiency (1), and tumour (1). All patients with chronic liver disease had experienced at least one complication, examples of which included encephalopathy, bacterial peritonitis, ascites, variceal bleeding and septicaemia. Serious postoperative complications included acute rejection of the transplanted liver, renal and liver failure that responded to intensive care support and medical management. One patient died on the 11th postoperative day with complications of bleeding oesophageal ulcer, shock and fungaemia. The remaining patients are alive and well 1-31 months after transplantation.
Medical education--maladies, myths and misconceptions.
Explore the source record for details and available documents.
National strategy for viral hepatitis: recommendations and guidelines for management in South Africa.
Explore the source record for details and available documents.
Purification of human erythrocyte porphobilinogen deaminase.
Human erythrocyte porphobilinogen deaminase was isolated using ammonium sulphate fractionation and heat treatment, Sephadex G-25 and G-100 chromatography, di-ethylamino-ethyl anion-exchange chromatography, chromatofocusing over a pH gradient of 7-4 and, finally, hydrophobic interaction chromatography on a phenyl-Sepharose column. The enzyme appeared pure as judged by sodium-dodecylsulphate-polyacrylamide gel electrophoresis with silver staining, and yielded a 7 115-fold purification.
Subcellular distribution of asialoglycoprotein receptor in liver regeneration.
Asialoglycoprotein (ASGP) receptor specific activity was determined directly using a radiolabelled ligand (asialoorosomucoid) binding assay in various fractions of rat liver cells before and 24 hours after two-thirds partial hepatectomy. The specific activity of ASGP receptor in the plasma membrane fraction was significantly reduced 24 hours after partial hepatectomy. In an attempt to identify a subgroup of receptor involved in intercellular recognition the calcium-dependent ASGP receptor was re-assayed after pre-incubation in ethylenediaminetetra-acetic acid. This revealed significant amounts of additional receptor in microsomal preparations but not in plasma membrane fractions. Cryptic receptor levels were not affected by partial hepatectomy. Plasma membrane-bound receptor was significantly decreased in regenerating liver.
Glutathione S-transferases YcYfetus and YcYc--kinetic and inhibitor studies relating to their glutathione peroxidase activities.
The kinetic properties of the glutathione (GSH) peroxidase activities of GSH S-transferases YcYfetus and YcYc were compared. The catalytic efficiency of the fetal iso-enzyme with cumene hydroperoxide as substrate was approximately four times higher than the other. The effects of the non-substrate ligand rose-Bengal as well as the substrate ligands sulphobromophthalein and acrolein on the GSH peroxidase activity of these two iso-enzymes were also investigated. Depending on the ligand, the inhibition profiles of these two iso-enzymes when measured with either the peroxidase substrate, cumene hydroperoxide or the standard GSH S-transferase substrate 1-chloro-2,4-dinitrobenzene were found to be either very similar (sulphobromophthalein) or markedly different (rose Bengal and acrolein). Significantly, the GSH peroxidase activity of the fetal iso-enzyme was far less susceptible to inhibition by the teratogen, acrolein, than that of the YcYc isoenzyme. It is therefore attractive to suggest that should a similar situation arise in vivo, this resistance to peroxidase inhibition may play a role in preventing the fetotoxic effects of acrolein.
Immunohistologic localization of alpha, mu, and pi class glutathione S-transferases in human tissues.
Human alpha, pi, and mu class glutathione S-transferases (GSH S-T) have been localized immunohistologically in a variety of organs. Alpha GSH S-T are found principally in hepatocytes, proximal convoluted tubules of kidney, the deep reticular layer of the adrenal gland, interstitial cells of the testis, and oxyntic cells of the stomach. The pi GSH S-T are present in relative abundance in ductular, as opposed to parenchymal cells in the liver, pancreas, salivary glands, and kidney. The presence of mu GSH S-T in the tissues of certain patients and its absence in the same tissues from other patients has been demonstrated. The pi GSH S-T seems to be most persistently and strongly expressed in tumors but alpha GSH S-T are also found in some neoplasms whereas the mu GSH S-T are occasionally present when the other two transferases are weak or absent.
Cyclosporin A in non-dietary IgY cirrhosis.
Explore the source record for details and available documents.
Twenty-one percent partial hepatectomy. In vivo rat model for the study of liver regeneration.
We describe a new model of submaximal stimulation of liver regeneration in the rat. Removal of the right lateral lobes in the rat produced a 21% hepatectomy. The measurement accuracy of the incorporation rate of [14C]thymidine into DNA 24 h after 21% hepatectomy (n = 32) was less than that after the standard 34% hepatectomy (n = 32), with S.D./mean being 35% and 130%, respectively (F-test, p less than 0.025). This model was able to detect regeneration-stimulation activity present in liver cytosol extract and serum of 68% hepatectomized rats. Using this model we identified a subfraction of rat serum achieved after treatment of serum with ethanol and ion-exchange column, which had a highly stimulatory effect. Stimulation obtained with serum from hepatectomized pigs showed that these factors are not species specific.
Amino acids fail to prevent halothane depression of albumin synthesis: studies in the isolated perfused rat liver.
Halothane (1.3 MAC) and ethanol (0.4%) depress albumin synthesis in isolated perfused rat livers (IPRLs). Addition of amino acids prevents depression by ethanol. We have examined the effects of amino acids on albumin synthesis by IPRLs exposed to halothane. Seventeen livers were perfused with a mixture of rat erythrocytes and rabbit plasma. Five were exposed to oxygen/carbon dioxide alone and 12 to oxygen/carbon dioxide with 1.5% halothane. A mixture of 10 essential amino acids was added to the perfusate of six of the halothane-exposed livers to a concentration approximately 10 times the normal rat plasma level. Perfusate concentrations of newly synthesized albumin were measured by radial immunodiffusion, and the rate of synthesis for the 4.25-h study period was calculated. The mean +/- SEM albumin synthetic rate (mg/h per 300-g rat) in the control group (12.13 +/- 1.36) was significantly greater than in the group receiving halothane alone (6.98 +/- 0.92). Amino acid treatment failed to prevent halothane depression of albumin synthesis (8.68 +/- 0.84). Thus, although amino acids block ethanol depression of albumin synthesis, we could show no such effect in rat livers exposed to halothane.
Primary biliary cirrhosis. A retrospective survey at Groote Schuur Hospital, Cape Town.
Primary biliary cirrhosis (PBC) or chronic non-suppurative destructive cholangiohepatitis is rare in southern Africa. Eight patients with this diagnosis were identified and fully investigated at Groote Schuur Hospital between 1980 and 1988. Seven patients were female, all were white or coloured, and their ages ranged from 49 years to 80 years. All patients presented with a history of malaise, fatigue, night sweats and pruritus, which had been present for 3 months--12 years before diagnosis of PBC. Initial misdiagnosis had resulted in unnecessary invasive investigations including laparotomies. Signs of chronic liver disease, such as xantholasmas, evidence of pruritus, the sicca syndrome or hepatomegaly, were invariably present. Marked elevation of serum alkaline phosphatase level and IgM were present in all cases. Antimitochondrial antibodies were positive in significant titre in 7 of the 8 patients. Liver biopsies demonstrated stage II-III disease in all patients. Therapy was chiefly supportive and symptomatic although most patients received immunosuppressive agents. Despite the late presentation, the subsequent course was similar to that seen elsewhere where patients are recognised earlier.
Retrospective survey of drug-induced liver disease at Groote Schuur Hospital, Cape Town--1983-1987.
In a survey of patients admitted to the medical and surgical wards of Groote Schuur Hospital during the 5-year period 1983-1987 38 patients with severe drug-induced hepatitis were identified. Fifty-three per cent of these reactions were caused by anti-tuberculosis drugs, 21% to phenytoin and 11% to methyldopa. Whereas 82% of the patients were jaundiced, only one-third had gastro-intestinal symptoms and/or fever and only 24% had a rash. Twenty-six per cent of patients were encephalopathic on admission. The overall mortality rate was 24%. Forty per cent of patients with hepatitis caused by anti-tuberculosis therapy died. Many patients had continued to receive therapy despite signs of liver disease. These findings underline the need for a high index of suspicion in the diagnosis of drug-induced liver disease and for early withdrawal of the offending agent(s).
Monocyte-macrophage release of IL-1 is inhibited by type-1 plasminogen activator inhibitors.
Interleukin-1 (IL-1) release from monocyte-macrophages (Mo) appears dependent on pericellular proteolysis mediated by plasmin. Thus plasminogen activator inhibitors (PAI) which bind the serine proteases responsible for the conversion of plasminogen to plasmin, may inhibit IL-1 release from Mo. We have examined the effect of purified PAI from a hepatoma cell line Hep G2, on IL-1 release from Mo with secondary effects on lymphocyte proliferation in vitro. Fast acting inhibitors of both urokinase (u-PA) and tissue plasminogen activator (two chain t-PA) were noted in harvest fluids of Hep G2 cells. These inhibitors were stable at pH 3 but lost activity at 45 degrees C. They were SDS-stable and migrated with Mr53 and 104 kDa. These properties conformed to characteristics of type-1 plasminogen activator inhibitor (PAI-1). Partially purified PAI-1 added to human Mo cultured on 125I fibrin layer both in the presence and absence of plasminogen inhibited secretion of IL-1 by Mo in response to LPS. This effect, however, did not correlate with the inhibition of plasminogen dependent fibrinolysis. This suggested a degree of sequestration and inaccessibility of membrane bound u-PA of LPS activated Mo to PAI-1. PAI-1, in addition, inhibited mitogen stimulated peripheral blood mononuclear cell (PBMC) proliferation at similar concentration ranges. This effect was abrogated by the addition of specific antisera to PAI-1. PAI-1 may be released as part of an acute phase response. In addition to influencing fibrinolysis, PAI-1 may constitute a negative feedback pathway on Mo IL-1 release and subsequent immune activation in vivo.
Liver tumours and the contraceptive pill: Controversies in aetiology, diagnosis and management.
Six female patients seen at Groote Schuur Hospital between 1973 and 1977, with the types of liver lesion that have been linked aetiologically with the contraceptive pill, are described. Four had focal nodular hyperplasia (1 with spontaneous rupture), and 1 patient had a hepatocellular carcinoma. The sixth patient had spontaneous rupture of the liver but no tumour was demonstrated. Based on this experience and a review of the literature, controversies in aetiology, diagnosis and managment are presented. A defined management policy is proposed for the benign lesions, a less aggressive approach being advocated for focal nodular hyperplasia than for hepatic adenoma.