Fatal reactivation of precore mutant hepatitis B virus associated with fibrosing cholestatic hepatitis after bone marrow transplantation.
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Bone Marrow Transplantation↗
Biomedical subjects
W G Cooksley
Publications and source records attributed to W G Cooksley.
Establishment of a cell line from a hepatocellular carcinoma from a patient with hemochromatosis.
We describe the establishment and characterization of a novel hepatoma cell line. This cell line, designated RBHF-1, was established from a hepatocellular carcinoma of a 67-yr-old man with a history of genetic hemochromatosis. At this writing, the cells have been maintained in RPMI-1640 tissue-culture medium and fetal calf serum without any additional supplements for 30 mo. The cells form colonies on soft agar and are not tumorigenic in nude mice. The cell line is polymorphic and displays characteristics of mature hepatocytes by synthesizing albumin, alpha 2-macroglobulin, fibronectin and alpha-fetoprotein. Cytogenetic analysis shows multiple chromosomal aberrations, with a consistent deletion in the long arm and deletions or rearrangements in the short arm of chromosome 1. There is no evidence for hepatitis B or hepatitis C virus infection of the cell line. The cells contain no detectable intracellular iron after staining with Perls' stain. Unlike other hepatoma cell lines, there is no detectable binding of epidermal growth factor to RBHF-1 cells. This is the first cell line to be established from a patient with hemochromatosis, and it provides a potentially important model for the study of hepatocyte transformation in association with iron overload.
Aged↗
Infection of human bone marrow stromal cells by hepatitis B virus: implications for viral persistence and the suppression of hematopoiesis.
Suspension cultures of bone marrow cells (BMC) were challenged with hepatitis B virus (HBV) to study interactions between the virus and the nonadherent and adherent BMC populations. Virus-challenged BMC developed an adherent stromal layer that differed in cellular composition from that of mock-infected cultures, showing a threefold increase in cells of the monocyte-macrophage lineage with an accompanying decrease in cells of the granulocytic lineage. Both viral envelope hepatitis B surface and core antigen expression was detected in adherent and nonadherent cell populations up to 10 days after virus challenge, which decreased thereafter. HBV DNA was still detectable in adherent cells 3 weeks after virus challenge, as shown by polymerase chain reaction analysis. These data indicate that HBV can infect not only bone marrow colony-forming cells but also the stromal cell populations involved with the regulation of hematopoiesis in vivo. Such virus-cell interactions could contribute to the immune dysfunction and bone marrow failure occasionally reported for patients with HBV infection as well as acting as an important site for HBV latency and persistence.
Bone Marrow↗
p53 gene in hepatocellular carcinomas from Australia.
The p53 protein is now well established as a crucial player in regulation of cell growth. Mutations arising in the coding sequences of its gene have been demonstrated in a wide variety of human tumors, including hepatocellular carcinoma (HCC). Our previous studies have shown that codon 249 mutations, the most common mutation of the p53 gene in HCCs, did not occur in our group of patients. To examine the prevalence of p53 mutations in other areas of the p53 gene, PCR and direct sequencing were carried out on these samples covering the four highly conserved regions of the gene between exons 5 and 8. Liver samples were obtained from both HBV+ and HBV- patients in a variety of ethnic groups. Primers to the flanking regions of exon 5, 6, 7, and 8 were used in PCR to amplify these exons. Following purification, the products were sequenced in both directions by cycle sequencing. In 15 HCCs examined, no mutations in these exons of the p53 gene were found. This suggests a less important role for p53 in development of HCC in this group of patients than in patients from other areas of the world.
Australia↗
Histological patterns of prolonged hepatitis C infection.
Liver biopsies from 63 patients with hepatitis C virus (HCV) infection have been studied. 31 were asymptomatic and had been detected by a variety of screening programs, and most of the other 32 had complained of vague symptoms only. In 57 patients a confident estimate of the duration of infection was able to be made (ranging from 12 months to over 38 years) and 73% of these had been infected for over 5 years. The most common histological pattern observed was a low-grade panacinar hepatitis. This affected 74.6% of all biopsies, and 43% of this group had been infected for over 10 years. Severe chronic active hepatitis and/or cirrhosis occurred in only 8% of the whole series, and in 16.7% of those infected for over 10 years. This incidence of serious sequelae in chronic HCV infection is much lower than previously reported, probably reflecting the methods of patient selection, and may represent more accurately the natural history of the disease in this community. The occurrence of a number of characteristic histological features (lymphoid follicles and aggregates, steatosis, Kupffer cell prominence, and apoptotic or acidophilic bodies) was confirmed, the constellation of which is highly suggestive of HCV infection. It is suggested that apoptosis may play an important role in the perpetuation of HCV as a chronic infection.
Adult↗
Failure to detect measles virus sequences in lymphocytes of patients with multiple sclerosis.
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Humans↗
Distribution of body water in patients with cirrhosis: the effect of liver transplantation.
We compared total body water and intracellular-extracellular distribution of body water between male patients with mild liver disease without ascites (n = 9), male patients with severe liver disease and gross ascites (n = 6) and a group of age-, sex-, height- and weight- matched controls (n = 6). In addition, we documented the effects of liver transplantation on intracellular, extracellular and total body water in 12 patients (6 men and 6 women) by means of deuterium oxide dilution and whole-body potassium counting. We saw no significant difference in total body water between the healthy controls, patients without ascites and patients with ascites (46.5 +/- 9.2 kg, 45.4 +/- 6.6 kg and 50.4 +/- 5.1 kg, respectively), although, as expected, extracellular water was increased in patients with ascites compared with healthy controls and cirrhotic patients without ascites (36.9 +/- 6.5 kg vs. 25.4 +/- 4.4 kg, p = 0.005; and 36.9 +/- 6.5 kg vs. 27.0 +/- 5.3 kg, p = 0.002, respectively). We found no difference between non-ascitic patients and healthy controls (25.4 +/- 4.4 kg vs. 27.0 +/- 5.3 kg). However, intracellular water was significantly reduced in patients with severe liver disease compared with that in controls (13.6 +/- 3.3 kg vs. 21.5 +/- 4.2 kg, p = 0.005) or patients without ascites (13.6 +/- 3.3 kg vs. 18.3 +/- 2.9 kg, p = 0.01). The reduction of intracellular water appears to be due to loss of body cell mass.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Allotype distribution of human T cell receptor beta and gamma chain genes in Caucasians, Asians and Australian aborigines: relevance to chronic hepatitis B.
RFLPs of TCR beta and gamma genes have been analyzed in chronic HBV carriers of three different ethnic populations to determine if there is an association of TCR allotypes with the development of chronic hepatitis B. The RFLPs of TCR beta and gamma genes were defined respectively by BglII and PvuII genomic fragments on Southern blots. These methods allow allotype assignment. The distribution of TCR beta alleles showed ethnic variation, with one allele significantly decreased in Australian Aborigines, but there was no association with chronic hepatitis B. The distribution of TCR gamma alleles did not show ethnic variation. However, a significant frequency decrease of one allele occurred in Aboriginal HBV carriers, suggesting the possibility of involvement of TCR gamma allotypes in the development of the chronic HBV carrier state in Australian Aborigines.
Alleles↗
Loss of somatic heterozygosity in hepatocellular carcinoma.
Loss of tumor suppressor genes is involved in the mechanism of tumorigenesis of many solid tumors. We tested 9 hepatitis B virus (HBV)-positive and 10 HBV-negative hepatocellular carcinomas for loss of somatic heterozygosity using 14 polymorphic probes mapping to chromosomes 4, 11, 13, and 17. Losses were found on all chromosome arms tested. The highest frequency of loss was observed at the D13S1 locus (67%) at band 13q12. Losses were also observed at three other loci on 13q. Twenty-one % of informative cases showed loss on 17p using the probe pYNZ22 which maps near the p53 locus. Losses on 4q were infrequent with 17% found at one locus and no loss at two others. The retinoblastoma gene and the locus on 17p were only inactivated in our HBV-negative tumors, although the numbers were too small for statistical significance. For all loci tested, we found no significant differences in the frequency of losses with HBV status, ethnic background, cirrhosis, grade of tumor, or presence of hemochromatosis.
Adult↗
Poor response to a recombinant hepatitis B vaccine in dialysis patients.
Eighty-three dialysis patients were inoculated with 20 micrograms of the recombinant derived hepatitis B vaccine Engerix-B at o, I and 6 months. Twenty-seven (32.5%) became seropositive for anti-HBs antibody after the third inoculation. Of the 56 non-responders, 48 received a 40 micrograms booster dose of vaccine 6 weeks after completion of the initial course and a further eight seroconverted. Six months after the third inoculation only 18/71 patients retested (25.3%) had demonstrable antibodies. We were unable to identify clinical or laboratory parameters separating responders from non responders to the vaccine. We recommend regular checks of anti-HBs status of vaccinated patients as it cannot be assumed that even initial responders retain their immunity. Those infection control procedures known to have decreased the incidence of hepatitis B infection in dialysis units should not be relaxed.
Adult↗
Prophylactic treatment regimens for the prevention of hepatitis A. Current concepts.
Hepatitis A virus (HAV) occurs worldwide. In developing countries the virus is endemic, with the majority of the population being exposed to it in childhood, when the infection usually causes, at the most, a mild anicteric illness. In developed countries the majority of HAV infections occur at a later age, often in adults, especially those with a history of recent travel to developing countries. In adults, HAV infection usually causes a symptomatic icteric illness. In addition to community sanitation and hygiene measures, prophylactic prevention of hepatitis A infection can be achieved by 2 methods. The first is the established and widely used method of passive immunisation using human immune globulin from pooled serum. Indications for the use of human immune globulin are: (a) travellers who will be exposed to unhygienic conditions in high risk countries; and (b) contacts of patients with acute hepatitis A infection, in certain circumstances. The second method currently undergoing research, and trials, is active immunisation using either live-attenuated or killed vaccines, which have given encouraging results in a number of trials. Further vaccines, using molecular biology techniques, are currently being developed.
Antibodies↗
The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.
Forty-two patients with nonalcoholic steatohepatitis were followed for a median of 4.5 yr (range = 1.5 to 21.5 yr). Except for two patients with lipodystrophy, all were obese; 35 of 42 were women, 26 of 32 were hyperlipidemic and 15 were hyperglycemic. Upper abdominal pain was the most common reason for presentation. Initial liver biopsy specimens showed the presence of macrovesicular fatty infiltration, lobular (acinar) inflammation, apoptosis, Mallory bodies (in four cases) and fibrosis (in 18 cases). Cirrhosis was present at initial diagnosis in one subject and in another two subjects liver biopsy showed marked fibrosis with disturbed architecture. Serial liver biopsy specimens revealed minimal or no apparent progression of the disorder in most of the patients, in keeping with their benign clinical course. However, one patient showed progression from fibrosis to cirrhosis during the 5-yr observation period, and in the patients with extensive fibrosis the liver disease evolved from one of active inflammation to one of inactive cirrhosis without fat or inflammation. The patient with cirrhosis later died of hepatocellular carcinoma. The severity or type of hepatic change did not correlate with the degree of obesity, hyperlipidemia or hyperglycemia. However, in individual patients, poorly controlled diabetes and rapid weight loss preceded the onset of steatohepatitis. We conclude that nonalcoholic steatohepatitis is a cause of hepatic inflammation histologically resembling that of alcohol-induced liver disease but usually slowly progressive and of low-grade severity. However, the disorder may ultimately result in cirrhosis. Nonalcoholic steatohepatitis should be distinguished from alcoholic steatohepatitis and recognized as a further cause of "cryptogenic cirrhosis."
Adolescent↗
The absence of hepatitis B virus DNA in hepatitis B e antigen positive sera from chronic hepatitis B surface antigen carriers in China.
Sera from 20 Chinese patients with chronic hepatitis B were examined for hepatitis B e antigen and hepatitis B virus (HBV) DNA. There was considerable discordance with HBV DNA not being detectable in 10 out of 13 (77%) patients who were hepatitis B e antigen positive. Further testing for anti-HBe and HBV-DNA polymerase activity confirmed the results. Possible reasons for this discordance are discussed but neither hepatitis D (delta) infection nor the acquired immunodeficiency syndrome (AIDS) could be implicated.
Adult↗
Discordance of hepatitis B e antigen and hepatitis B viral deoxyribonucleic acid.
Sera from 899 hepatitis B surface antigen (HBsAg) carriers from four separate ethnic groups (Caucasian, Australian Aboriginal, Melanesian, and Asian) were studied for their correlation for hepatitis B virus deoxyribonucleic acid (HBV DNA) and hepatitis B e antigen (HBeAg). Discordance, as signified by the absence of HBV DNA despite the presence of HBeAg, was unusual in Caucasians but frequently occurred in the other three ethnic groups (11-25%). Analysis by age showed that it occurred occasionally during childhood and, in this age group, may simply be part of the process of seroconversion with impending loss of HBeAg, whereas its greater prevalence in patients with liver disease may have a different mechanism. In sera obtained from Melanesians with hepatocellular carcinoma and Asians with chronic hepatitis, discordance was a common feature with HBV DNA being undetectable in those with HBeAg in 87% and 72%, respectively. A number of important implications flow from these observations pertinent to the use of HBeAg to detect replicating virus and the prognostic significance of HBeAg in HBsAg carriers when HBV DNA is undetectable.
Child↗
Improvement in chronic hepatocerebral degeneration following liver transplantation.
Chronic progressive hepatocerebral degeneration with spastic paraparesis, dementia, dysarthria, ataxia, tremor, and neuropsychiatric symptoms follows long-standing portal-systemic shunting, is associated with structural changes in the central nervous system, and does not respond to conventional therapy for hepatic encephalopathy. A case of advanced chronic liver disease with severe, progressive hepatocerebral degeneration after 23 yr of portal-systemic shunting is reported in whom there was significant objective improvement in intellectual function and in the chronic neurological signs 3 mo after orthotopic liver transplantation and further improvement 12 mo after transplantation.
Adult↗
Dose-dependent pharmacokinetics of caffeine in humans: relevance as a test of quantitative liver function.
Caffeine clearance was determined in 13 healthy control subjects and in 13 patients with histologically proven cirrhosis. On separate occasions, 70 mg, 200 mg, and 300 mg single doses of anhydrous caffeine were administered orally with decaffeinated coffee to each subject. Subjects were analyzed individually, acting as their own controls, thus reducing interindividual variability. The present study showed that caffeine exhibited dose-dependent pharmacokinetics, particularly in subjects who showed high initial clearance with the low dose (70 mg) of caffeine. There was a significant decrease in caffeine clearance with increasing dose from 70 mg to 300 mg (n = 26, p less than 0.01, Dunnett's test), indicating saturable caffeine metabolism in the dose range tested. These findings imply that if caffeine is to be used as a guide to deteriorating liver function, serial caffeine clearance estimations should be performed in each individual subject, with use of the same dose of caffeine each time.
Administration, Oral↗
Randomised controlled trial of recombinant human interferon -alpha A for chronic active hepatitis B.
The efficacy of interferon treatment for Australian patients with chronic active hepatitis B (CAH-B) was assessed by a three-centre randomised controlled trial in Sydney and Brisbane. Thirty patients (29 with histologically-proven CAH-B with and without cirrhosis and one with chronic persistent hepatitis) were allocated to receive either thrice weekly intramuscular injections of recombinant human leucocyte interferon -alpha A (either 2.5, 5.0 or 10.0 million units/m2) for six months followed by 12 months of observation, or to be observed for 18 months without active treatment. Three of 23 treated patients but none of seven controls underwent clinical, biochemical and histological resolution of their disease with loss of HBsAg, HBeAg and HBV-DNA from serum. An additional six treated and two control patients underwent a sustained partial remission of their disease. This was characterised by resolution of symptoms and serum aminotransferase abnormalities in association with seroconversion from HBeAg positive to negative, loss of HBV-DNA from serum but persistent hepatitis B surface antigenaemia. In such patients, there was significant improvement in histological appearances but some necroinflammatory activity remained and fibrosis was unchanged. Although total response rates were similar in treated and control subjects, they appeared to occur earlier after interferon treatment. Treatment with interferon was associated with predictable but minor side effects that usually did not necessitate dose reduction and rarely compromised the patient's life style. Interferon is thus a feasible treatment for CAH-B. Complete responses occurred only in treated patients and partial responses appeared to occur earlier in treated than in untreated patients. However, differences in the partial response rate at 18 months were not significant and seroconversion from HBeAg positive to negative was not associated with complete histological resolution of disease activity. Hence, while interferon is a promising agent for treatment of CAH-B, efforts must continue to define more optimal treatment regimes and to identify those patients most likely to respond to this agent.
Adult↗
HBsAg-induced antigen-specific T and B lymphocyte responses in chronic hepatitis B virus carriers and immune individuals.
This report describes a study of in vitro proliferative and antibody responses to the hepatitis B virus surface antigen (HBsAg) of lymphocytes from chronic HBsAg carriers, subjects with naturally acquired immunity, and responders to the hepatitis B vaccine. Peripheral blood T and B lymphocytes were cultured with a wide range of concentrations of HBsAg (0.025-250 ng/ml). We were unable to detect HBsAg-specific proliferation or antibody synthesis in any of the subject groups studied, despite the use of a range of antigen concentrations, cell ratios and culture periods. The addition of recombinant interleukin 2 (rIL-2) or T cell growth factor at either initiation or day 3 of culture enhanced proliferative responses, but in an antigen-independent manner. In contrast to the proliferation observed following the addition of IL-2, the absence of responses to specific antigen suggest there may be low numbers of HBsAg-specific precursors in the peripheral blood.
Adult↗