TNF alpha in stool as marker of intestinal inflammation.
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Biomarkers↗
Biomedical subjects
G J Alexander
Publications and source records attributed to G J Alexander.
Effects of vasopressor agents and epoprostenol on systemic hemodynamics and oxygen transport in fulminant hepatic failure.
Hypotension is a serious complication in patients with fulminant hepatic failure, because it is associated with tissue hypoxia and a further compromise to end-organ function. In this study we investigated the effects of epinephrine and norepinephrine on hemodynamics and oxygen transport variables in 30 patients with fulminant hepatic failure. All had a mean arterial pressure of less than 60 mm Hg, despite adequate intravascular filling pressures. Both epinephrine (n = 15) and norepinephrine (n = 15) improved mean arterial pressure (p less than 0.001 epinephrine and norepinephrine), although this was not associated with a rise in oxygen delivery. Oxygen consumption fell (p less than 0.05 epinephrine, p less than 0.001 norepinephrine) because of a lower oxygen extraction ratio (p less than 0.01 epinephrine and norepinephrine). The addition of epoprostenol, a microcirculatory vasodilator, in 10 patients from each group led to an increase in oxygen consumption (p less than 0.001 epinephrine and norepinephrine) because of a rise in oxygen delivery (p less than 0.05 epinephrine, p less than 0.01 norepinephrine) and oxygen extraction ratio (p less than 0.01 epinephrine, p less than 0.001 norepinephrine), without a fall in mean arterial pressure. The fall in oxygen consumption after the institution of vasopressor therapy could exacerbate tissue hypoxia and thus contribute to further organ damage in an already susceptible patient. In patients with fulminant hepatic failure who are given vasopressor support, the addition of epoprostenol may prevent the development of tissue hypoxia.
Adolescent↗
Cytomegalovirus infection persists in the liver graft in the vanishing bile duct syndrome.
Cytomegalovirus infection is one factor implicated in the cause of the vanishing bile duct syndrome complicating liver transplantation. To further investigate the role of cytomegalovirus in this syndrome, we studied serial liver biopsy material by in situ hybridization for cytomegalovirus DNA using a highly sensitive technique that allows the localization of viral replication. Cytomegalovirus DNA was identified in hepatocytes in 10 of 12 patients with the vanishing bile duct syndrome, 1 of whom had no serological evidence of cytomegalovirus infection. It was also present in all 18 patients with uncomplicated cytomegalovirus infection but was not identified in any of 10 subjects with transplants who had neither complication. Nine of the patients in this series underwent a diagnostic liver biopsy at 1 wk and subsequently had cytomegalovirus infection develop; cytomegalovirus DNA was identified in liver tissue of all nine patients, indicating that cytomegalovirus replication commences at an early stage. In those with uncomplicated cytomegalovirus, infection occurred earlier (p less than 0.05) but was eliminated more quickly (p less than 0.0005), and the number of infected hepatocytes was greater (p less than 0.05) when compared with those with the vanishing bile duct syndrome; in these, cytomegalovirus DNA was detectable until death or retransplantation. Cytomegalovirus DNA was never identified in either biliary or endothelial tissue. These data indicate that the vanishing bile duct syndrome is associated with persistent cytomegalovirus replication within hepatocytes.
Cholestasis↗
Significance of serum IgM anti-HBc in chronic hepatitis B virus infection.
Because of widely differing reports on the significance of IgM anti-HBc in chronic hepatitis B virus (HBV) infection, paired sera and liver biopsies from 49 patients with chronic HBV infection were analysed for serum IgM anti-HBc, HBsAg titre, HBeAg/anti-HBe, HBV DNA, serum aspartate transaminase, intrahepatic HBcAg expression, and liver histology. High levels of IgM anti-HBc, in the diagnostic range of acute hepatitis B (greater than 1.2), were detected in seven patients (14.3%) and a total of 34 patients (69.6%) had an index of more than 0.2. No correlation was found between IgM anti-HBc and the serum markers of active viral replication or HBsAg titre but it correlated significantly with intrahepatic expression of cytoplasmic HBcAg (r2 = 0.165, P = 0.002). IgM anti-HBc also correlated with active liver histology (P = 0.015) but there was a considerable overlap of the IgM anti-HBc index values between the various disease groups, indicating a poor specificity. Serial assessment of IgM anti-HBc in eight patients treated with interferon-alpha (four responders) showed an increase in IgM anti-HBc in three out of four patients corresponding to the e-seroconversion period followed by a drop in IgM anti-HBc levels. However, an increase in IgM anti-HBc was also seen in one non-responder, indicating that this feature is not unique to interferon-alpha responders. These data indicate that serum IgM anti-HBc cannot be used alone as a certain diagnostic measure of HBV replication nor in the prediction of liver histology.
Adolescent↗
High-level expression of hepatitis B viral antigens in fibrosing cholestatic hepatitis.
The expression of hepatitis B viral antigens was quantified in liver tissue from four transplant recipients with fibrosing cholestatic hepatitis (FCH) and compared with five other transplant recipients who did not develop this syndrome and 30 patients with chronic hepatitis B virus (HBV) infection. As measured by radioimmunoassays, the liver tissue from patients with FCH had significantly greater amounts of both hepatitis B surface antigen (HBsAg) and nucleocapsid antigens than to transplant patients without this syndrome (P less than 0.01) or patients with chronic HBV infection (P less than 0.001). Intrahepatic expression of pre-S1/pre-S2 in FCH was also extensive with a distribution parallel to that of HBsAg. High-level expression of intrahepatic HBsAg and hepatitis B core antigen in the explanted liver was associated with subsequent development of FCH in the liver graft, suggesting that viral/host factors may also be important. This pattern of intrahepatic hepatitis viral antigen expression, by analogy with Chisari's transgenic mice model and Roingeard's HBV-transfected HepG2 cell model, may be the cause of direct hepatocytopathic injury in this condition.
Adult↗
Immunoglobulin A antibody to a 200-kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis.
Considerable clinical and experimental evidence points to the importance of immune responses in the development of alcoholic liver disease. In the present study it was investigated whether circulating antibodies from patients with alcoholic liver disease recognize acetaldehyde-liver protein adducts. Cytosolic and microsomal fractions from livers of Wistar rats or from normal human liver were incubated with acetaldehyde (0.5-2.5 mmol/L) and/or cyanoborohydride (100 mmol/L) then analysed by immunoblotting. Cytosolic fractions that had been incubated with acetaldehyde and cyanoborohydride expressed a 200-kilodalton protein antigen not present in untreated fractions or fractions incubated with acetaldehyde or cyanoborohydride alone. The 200-kilodalton antigen was recognized by immunoglobulin (Ig)A antibodies in a large proportion of sera from patients with alcoholic hepatitis (70%, n = 23), but in significantly smaller proportions of sera from patients with alcoholic cirrhosis without hepatitis (30%, n = 10; P < 0.05), heavy drinkers without overt liver disease (20%, n = 10; P < 0.02), patients with nonalcoholic liver disease (35%, n = 17; P < 0.05), or normal control subjects consuming moderate quantities of alcohol (25%, n = 20%; P < 0.005). These results indicate that IgA antibodies to a 200-kilodalton acetaldehyde-protein adduct are present in a large proportion of patients with alcoholic liver disease and in a significantly smaller proportion of other individuals.
Acetaldehyde↗
Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications.
The implications of hepatitis B virus (HBV) reinfection after liver transplantation were studied in 29 patients followed for 1.7-15 years. Of 20 patients with HBV infection alone, nine were HBeAg and HBV DNA seronegative and 11 had evidence of HBV replication as measured by HBeAg or HBV DNA seropositivity. Nine patients had co-existing HBV and delta virus (HDV) infection. Five patients became HBsAg seronegative after transplantation (four immediately and one after an hepatitic episode). Of the 20 patients with HBV infection alone, 17 had evidence of viral replication after transplantation with markedly increased HBV DNA levels. Five patients with HDV infection had HBV DNA in serum, but in significantly lower amounts than in those with HBV infection alone. Twenty-five episodes of graft dysfunction attributed to recurrent HBV infection occurred in 19 patients (65.5%). Thirteen episodes (in 12 patients) were self-resolving acute hepatitic illnesses. Six patients had a rapidly progressive illness leading to graft loss within 6 weeks, with the distinctive histological features termed fibrosing cholestatic hepatitis (FCH). Liver function tests in these patients showed markedly abnormal serum bilirubin and prothrombin times, but only modest increases in serum transaminase levels. An additional six patients lost their graft as a consequence of HBV recurrence through various pathogenetic mechanisms including possible (but unproven) FCH, chronic active hepatitis or late-onset hepatic failure. Co-existing HDV infection appeared to confer some medium-term protection from graft loss.
Adult↗
Interferon-gamma receptor expression in chronic hepatitis B virus infection.
It is known that interferon-gamma (IFN gamma) is not effective in inducing a sustained inhibition of HBV replication in patients with chronic HBV infection in contrast to interferon-alpha (IFN alpha). To determine whether this was related to IFN gamma receptor (IFN gamma-R) underexpression, binding characteristics of IFN gamma to peripheral blood lymphocytes were studied in chronic HBV infection using radioiodinated recombinant IFN gamma. Peripheral blood lymphocytes from patients with chronic HBV infection (n = 20), normal healthy controls (n = 12) and patients with non-viral related chronic liver disease expressed a similar number of IFN gamma-R (medians (ranges): 1891 (1581-2515); 1916 (1589-2441); 1893 (1692-2104) sites/cell, respectively, p = N.S.) with a similar dissociation constant (Kd approximately 0.7-2.7 nM). There was no correlation between IFN gamma-R expression and serum transaminase, serum HBsAg and HBV-DNA titres and liver histology. IFN alpha therapy in vivo also did not enhance IFN gamma-R expression (n = 3). There is therefore, no evidence from this data that IFN gamma-R is underexpressed in patients with chronic HBV infection to account for the difference in clinical response to these two forms of therapy.
Adult↗
Evidence that hepatitis D virus needs hepatitis B virus to cause hepatocellular damage.
Serial liver biopsy specimens from 11 patients who had liver transplants after hepatitis D virus (HDV)-related end-stage liver disease developed were examined, allowing a novel opportunity to study the evolution of HDV infection in relation to hepatitis B virus (HBV) infection from the earliest stages. Hepatitis D virus antigen was detected in liver tissue in the absence of either tissue or serologic evidence of HBV recurrence within 3 months in all eight patients biopsied at that time. After serologic evidence of recurrent HBV infection in nine patients, there was a massive increase in hepatic expression of hepatitis D virus antigen and this was associated with the transient appearance of serum hepatitis D virus antigen in four patients. Coexpression of both HBV and HDV antigens in the liver was associated with the onset of lobular hepatitis, which progressed to chronic hepatitis in five patients. These findings indicate that HDV can survive and synthesize HDAg in the absence of detectable HBV, but when HBV replication increased to a detectable level, HDV replication was enhanced massively. Contrary to current thinking, the data suggest that HDV is not directly cytopathic and that HBV is an essential cofactor in the evolution of hepatocellular damage.
Adult↗
Modulation of hepatitis B viral antigen expression by immunosuppressive drugs in primary hepatocyte culture.
In one pattern of hepatitis B virus (HBV) recurrence following orthotopic liver transplantation--namely, fibrosing cholestatic hepatitis (FCH), the intrahepatic expression of HBV antigens was found to be markedly increased, suggesting that HBV may be directly cytopathic to the liver cells. Understanding how immunosuppressive drugs influence HBV may be of considerable clinical relevance in the treatment of patients with chronic HBV infection after liver transplantation. To determine how these drugs influence intrahepatic HBV antigen expression, hepatocytes isolated from patients with chronic HBV infection were incubated in the absence or presence of prednisolone (10(-6)-10(-10) M), methylprednisolone (10(-6)-10(-10) M), azathioprine (0.1-10 micrograms/ml), or cyclosporine (50-1000 ng/ml) and the amount of intracellular/secreted antigen was measured by radioimmunoassay. Intracellular HBsAg increased by 25.0-51.1% with prednisolone 10(-8)-10(-6) M (n = 14, P less than 0.05) and methylprednisolone 10(-9)-10(-6) M (n = 8, P less than 0.05). Immunocytochemistry of cytospins showed that the proportion of cells containing HBsAg increased by 20-38% with stronger staining, but the distribution of HBsAg remained diffusely cytoplasmic; the changes in intracellular pre-S1 and pre-S2 paralleled those of HBsAg. Secreted HBsAg was, however, not affected. There was also an increase in intracellular nucleocapsid antigens by 24.1-32.5% with an increase in hepatocytes containing nucleocapsid antigens by 8-18%. Methylprednisolone exerted similar effects to prednisolone. On the other hand, neither azathioprine (n = 11) nor cyclosporine (n = 12) had any effect on intracellular or secreted HBsAg or nucleocapsid antigens. These data indicate that corticosteroids, but not azathioprine or cyclosporine, enhance intracellular HBV antigen expression in this short-term culture system. This may be an important factor in the evolution of FCH and careful attention to the use of corticosteroids may be beneficial in patients with chronic HBV infection undergoing liver transplantation.
Adult↗
Differential effect of chronic hepatitis D virus infection on intrahepatic expression of hepatitis B viral antigen.
AIMS: To determine how chronic hepatitis D virus (HDV) infection affects intrahepatic hepatitis B virus (HBV) antigen expression. METHODS: Ninety eight liver biopsy specimens from 68 patients seropositive for total antibody to HDV were studied by immunohistochemistry, and the amount of HBV antigens was also quantified by radioimmunoassay in 12 patients and compared with 30 patients with chronic HBV infection. RESULTS: Forty nine of the 68 patients were positive for intrahepatic HDV antigen and only five were positive for HBV core antigen (HBcAg). HBV surface antigen (HBsAg) was present in 55 (80.9%) patients and was always cytoplasmic in distribution. Hepatic pre-S1 and pre-S2 expressions paralleled that of HBsAg, and were detected in 53 (77.9%) and 54 (79.4%) patients, respectively. There was no relation between the intrahepatic expression of HDV antigen and HBsAg/pre-S1/pre-S2. Follow up biopsy specimens in 25 patients showed either static or deteriorating histology while intrahepatic HDV antigen remained the same or fell. The patients with intrahepatic expression of HBcAg had either absent or noticeably decreased expression of HBcAg in their follow up biopsy specimens (median two years). In contrast, HBsAg/pre-S1/pre-S2 were the same or increased (p less than 0.001). Quantification of intrahepatic HBsAg in patients with chronic HDV infection (0.61 pg/hepatocyte, range: 0.05-1.08, n = 12) showed no difference with patients with chronic HBV infection alone (0.64 pg/hepatocyte, range: 0.02-1.02, n = 30, p = NS). CONCLUSION: These data indicate that chronic HDV infection suppresses intrahepatic expression of HBcAg but not HbsAg and pre-S antigens, suggesting a differential effect of chronic HDV infection on HBV gene expression.
Adult↗
Hepatitis B and delta virus infection among "at risk" populations in south east London.
STUDY OBJECTIVE: The hepatitis delta virus (HDV) contributes significantly to the morbidity and mortality of hepatitis B virus (HBV) infection, which is particularly prevalent among intravenous drug users and male homosexuals. A recent report has indicated that HDV first appeared in the South East London intravenous drug using population in 1982. The aim of the present study was to assess the prevalence of HDV in these two groups at risk of HBV infection in South East London. DESIGN: The study was a cohort analysis of HBV and delta virus serum markers, stratified temporally and with respect to intravenous drug use and sexual practice. SETTING: This was a population study of 372 consecutive intravenous drug users attending a local drug rehabilitation centre and 1481 subjects seen at a sexually transmitted disease clinic in the same area, during the years 1979 to 1988. MEASUREMENTS AND MAIN RESULTS: Of 372 intravenous drug users, 195 (52.4%) had evidence of current or past infection with HBV, of whom 17 had chronic HBV infection--a carriage rate of 8.7%. Twelve (70.6%) of these 17 also had chronic HDV infection--the first cases being identified in 1984. By comparison, 406 (27.4%) of the sexually transmitted disease clinic patients had been been exposed to HBV, 32 having chronic HBV: a carriage rate of 7.9% (7.5% v 9.4% among male homosexuals v male heterosexuals). Ten had been exposed to HDV (the first case in 1980) but only two (who did not admit to intravenous drug use) had chronic HDV infections (p less than 0.0005 v the rehabilitation centre patients). CONCLUSIONS: Although the HBV carriage rate is very similar in these two populations, chronic HDV infections were mainly confined to intravenous drug users. However, reports from the USA and France indicate spread of delta virus to the male homosexual community and, since there is clearly a pool of HDV in SE London, vaccination against HBV in these risk groups in likely to be cost-effective and should be actively encouraged.
Female↗
Association of type III cryoglobulinaemia and hepatitis C virus-related cirrhosis.
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Cryoglobulinemia↗
Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial.
OBJECTIVE: To see whether intravenous acetylcysteine would improve outcome in patients with fulminant hepatic failure after paracetamol overdose. DESIGN: A prospective randomised controlled study. SETTING: The Institute of Liver Studies, King's College Hospital, London. PATIENTS: 50 consecutive patients (21 male) aged 16-60 with fulminant hepatic failure after paracetamol overdose who had not previously received acetylcysteine. INTERVENTIONS: Conventional intensive liver care plus either acetylcysteine (25 patients) in the same dose regimen as used early after a paracetamol overdose, except that the infusion was continued until recovery from encephalopathy or death, or an equivalent volume of 5% dextrose (25 patients). MAIN OUTCOME MEASURES: Survival; incidence of cerebral oedema, renal failure, and hypotension requiring inotropic support; liver function as assessed by prolongation of the prothrombin time; and degree of encephalopathy. RESULTS: The rate of survival was significantly higher in the acetylcysteine treated group than in the controls (48% (12/25 patients) v 20% (5/25); p = 0.037, 95% confidence interval for difference in proportions surviving 3% to 53%). Acetylcysteine treated patients had a lower incidence of cerebral oedema (40% (10/25) v 68% (17/25); p = 0.047, 95% confidence interval for difference in incidence 2% to 54%), and fewer developed hypotension requiring inotropic support (48% (12/25) v 80% (20/25); p = 0.018, 95% confidence interval 7% to 57%). Rates of deterioration and recovery of liver function, however, were similar in the two groups. No adverse reactions to acetylcysteine were seen. CONCLUSIONS: Acetylcysteine is safe and effective in fulminant hepatic failure after paracetamol overdose.
Acetaminophen↗
Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure.
BACKGROUND: When administered early after an overdose of acetaminophen, intravenous acetylcysteine prevents hepatic necrosis by replenishing reduced stores of glutathione. How acetylcysteine improves the survival of patients with established liver damage induced by acetaminophen, however, is unknown. This study was undertaken to determine whether the beneficial effect of acetylcysteine under such circumstances could be due to enhancement of oxygen delivery and consumption. METHODS: We studied the effect of acetylcysteine on systemic hemodynamics and oxygen transport in 12 patients with acetaminophen-induced fulminant hepatic failure and 8 patients with acute liver failure from other causes. The acetylcysteine was given in a dose of 150 mg per kilogram of body weight in 250 ml of 5 percent dextrose over a period of 15 minutes and then in a dose of 50 mg per kilogram in 500 ml of 5 percent dextrose over a period of 4 hours; measurements were made before treatment began and after 30 minutes of the regimen. RESULTS: In the patients with acetaminophen-induced liver failure, the infusion of acetylcysteine resulted in an increase in mean oxygen delivery from 856 to 975 ml per minute per square meter of body-surface area (P = 0.0036), due to an increase in the cardiac index from 5.6 to 6.7 liters per minute per square meter (P = 0.0021). Mean arterial pressure rose from 88 to 95 mm Hg (P = 0.0054) despite a decrease in systemic vascular resistance from 1296 to 1113 dyn.sec.cm-5 per square meter (P = 0.027). There was an increase in oxygen consumption from 127 to 184 ml per minute per square meter (P = 0.0007) associated with an increase in the oxygen-extraction ratio from 16 to 21 percent (P = 0.022). The effects in the patients with acute liver failure from other causes were similar. CONCLUSIONS: The increase in oxygen delivery and consumption in response to acetylcysteine may account for its beneficial effect on survival in patients with fulminant hepatic failure induced by acetaminophen.
Acetaminophen↗
Treatment of HBV reactivation after withdrawal of immunosuppression.
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Chemical and Drug Induced Liver Injury, Chronic↗
Increased tumor necrosis factor-alpha receptor number in chronic hepatitis B virus infection.
Production of the antiviral cytokine, tumor necrosis factor-alpha is increased in chronic hepatitis B virus infection, and clinical studies of tumor necrosis factor-alpha have indicated a proviral effect at higher doses. To determine whether this might be related to abnormal cell surface tumor necrosis factor-alpha receptor expression, binding characteristics of cell surface tumor necrosis factor-alpha receptor on peripheral blood mononuclear cells in chronic hepatitis B virus carriers were studied using radioiodinated recombinant tumor necrosis factor-alpha. The specific binding curves generated were analyzed according to the method of Scatchard to determine cell surface receptor numbers and dissociation constants. A single class of cell surface tumor necrosis factor-alpha receptor was demonstrated on peripheral blood mononuclear cells and mononuclear subsets. The median number (range) of cell surface tumor necrosis factor-alpha receptors on peripheral blood mononuclear cells from controls (n = 11), chronic hepatitis B virus patients seropositive for hepatitis B virus DNA (n = 8) and seronegative for hepatitis B virus DNA (n = 8) were 2,329 (range = 1,538 to 3,133), 3,375 (range = 2,300 to 6,718) (p less than 0.01) and 3,113 (range = 2,229 to 5,246) (p less than 0.05) sites/cell, respectively. They all had similar dissociation constants of 8.4 x 10(-10) mol/L (range = 4.1 to 16.9), respectively. Further dissection of the peripheral blood mononuclear cells showed that this increase in cell surface receptor number was confined to the monocyte fraction (p less than 0.01). Plasma tumor necrosis factor-alpha levels in five patients with increased monocyte cell surface tumor necrosis factor-alpha receptor numbers were also elevated.(ABSTRACT TRUNCATED AT 250 WORDS)
Carrier State↗
Significance of IgM anti-hepatitis D virus (HDV) in chronic HDV infection.
Intrahepatic hepatitis D virus (HDV) antigen (HDAg) and serum HDV RNA are excellent markers of active HDV replication but the relation of IgM anti-HDV to HDV replication and histological activity is less certain. To further elucidate the significance of serum IgM anti-HDV, 90 paired sera and liver biopsies from 64 patients seropositive for total antibody to HDV were analysed for IgM anti-HDV, intrahepatic HDAg expression, and histological inflammatory activity. IgM anti-HDV was strongly associated with intrahepatic HDAg expression with a sensitivity of 94.1% but the assay lacked specificity since 14 out of 22 cases negative for intrahepatic HDAg were also positive for IgM anti-HDV. In 20 patients in whom follow-up biopsies and paired sera were available, two patients lost intrahepatic HDAg but paired serum remained IgM anti-HDV positive. Although the presence of serum IgM anti-HDV correlated significantly with a higher histological inflammatory activity (P = 0.001), there was a considerable overlap with the group seronegative for IgM anti-HDV, again indicating a poor specificity. This lack of specificity of IgM anti-HDV for both HDV replication and histological activity indicates that this assay provides no additional information over and above assay for total antibody to HDV.
Antigens, Viral↗