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M C Kew

Publications and source records attributed to M C Kew.

At least 19 recordsLinked to original sources
PubMed2006

Interaction between hepatitis B and C viruses in hepatocellular carcinogenesis.

Although hepatitis B (HBV) and C viruses (HCV) are, individually, major causes of hepatocellular carcinoma, the interaction, if any, between the carcinogenic effects of the two viruses is uncertain. Equal numbers of published studies have reported no risk interaction or a synergistic risk interaction. These conflicting results are explained by the rarity of concurrent infection with HBV and HCV in individuals without clinically evident liver disease, which severely limits the ability to accurately estimate the hepatocarcinogenic risk of dual infection compared with that of either infection alone. In an attempt to circumvent this difficulty, two meta-analyses have been performed, one based on studies published from a number of countries and the other on studies confined to Chinese patients. Both analyses concluded that a synergistic carcinogenic interaction existed between the two viruses and that the increased risk was super-additive but not multiplicative. If confirmed, this risk interaction will occur against a background of negative confounding effects on viral replication between HBV and HCV, which may be reciprocal. The mechanisms responsible for the carcinogenic interaction between the viruses are unknown. One possibility is that the increased incidence of cirrhosis with concurrent HBV and HCV infections acts as an even more potent tumour promoter than occurs with either virus alone. Synergism between the direct hepatocarcinogenic effects of the two viruses is another possible mechanism, but proof will have to await a fuller understanding of the pathogenetic mechanisms involved with the individual viruses.

Carcinoma, Hepatocellular↗
PubMed2006

Membranous obstruction of the inferior vena cava and its causal relation to hepatocellular carcinoma.

Although rare in most countries, membranous obstruction of the inferior vena cava (MOIVC) occurs more frequently in Nepal, South Africa, Japan, India, China, and Korea. The occlusive lesion always occurs at approximately the level of the diaphragm. It commonly takes the form of a membrane, but may be a fibrotic occlusion of variable length. Controversy exists as to whether MOIVC is a developmental abnormality or a result of organization of a thrombus in the hepatic portion of the inferior vena cava. The outstanding physical sign associated with MOIVC are large truncal collateral vessels with a cephalad flow. A dilated vena azygous is seen on chest radiography. Definitive diagnosis is made by contrast inferior vena cavography. The long-standing obstruction to hepatic venous flow causes severe centrolobular fibrosis and predisposes to the development of hepatocellular carcinoma (HCC). Percutaneous balloon angioplasty, transatrial membranotomy, or more complex vena caval and portal decompression surgery should be performed to prevent these complications. HCC occurs in more than 40% of South African Black and Japanese patients with MOIVC, but less often in other populations. It is thought to result from the tumour-promoting effect of continuous hepatocyte necrosis, although the associated environmental risk factors have not been identified.

Adult↗
PubMed2005

Relationship of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy.

SUMMARY: Phylogenetic analysis has led to the classification of hepatitis B virus into eight genotypes, designated A to H. The genotypes have differences in biological properties and show heterogeneity in their global distribution. These attributes of the genotypes may account not only for differences in the prevalence of hepatitis B virus mutants in various geographic regions, but also be responsible for differences in the clinical outcome and response to antiviral treatment in different population groups.

Antiviral Agents↗
PubMed2005

Hepatitis B virus and human immunodeficiency virus co-infection in sub-Saharan Africa: a call for further investigation.

A growing body of evidence indicates that human immunodeficiency virus (HIV)-positive individuals are more likely to be infected with hepatitis B virus (HBV) than HIV-negative individuals, possibly as a result of shared risk factors. There is also evidence that HIV-positive individuals who are subsequently infected with HBV are more likely to become HBV chronic carriers, have a high HBV replication rate, and remain hepatitis Be antigen positive for a much longer period. In addition, it is evident that immunosuppression brought about by HIV infection may cause reactivation or reinfection in those previously exposed to HBV. Furthermore, HIV infection exacerbates liver disease in HBV co-infected individuals, and there is an even greater risk of liver disease when HIV and HBV co-infected patients are treated with highly active anti-retroviral therapy (HAART). Complicating matters further, there have been several reports linking HIV infection to 'sero-silent' HBV infections, which presents serious problems for diagnosis, prevention, and control. In sub-Saharan Africa, where both HIV and HBV are endemic, little is known about the burden of co-infection and the interaction between these two viruses. This paper reviews studies that have investigated HIV and HBV co-infection in sub-Saharan Africa, against a backdrop of what is currently known about the interactions between these two viruses.

AIDS-Related Opportunistic Infections↗
PubMed2002

Lack of susceptibility of Chacma baboons (Papio ursinus orientalis) to hepatitis C virus infection.

The main reason to ascertain whether baboons are susceptible to infection with hepatitis C virus (HCV) is the need to replace chimpanzees, which are endangered, as an animal model for undertaking research into the biology and host-virus interactions of HCV, and for developing a vaccine against this virus. A second reason is that baboons are a possible source of xenografts for human liver transplantation. We inoculated serum containing HCV into four Chacma baboons and monitored them for 52 weeks for evidence of infection. Serum was tested for antibody to HCV, HCV RNA, and aminotransferase concentrations at 2-week intervals for 26 weeks and thereafter at 4-week intervals. Liver tissue was examined at 28 and 52 weeks for histopathological changes and viral RNA, and at 52 weeks for viral particles using electron microscopy. Reverse transcription-polymerase chain reaction assay was used to detect HCV RNA, and the results were confirmed by Southern hybridization. Serum aminotransferase concentrations remained within the normal range and liver histology was normal during the follow-up period. Passive transmission of anti-HCV to the baboons was observed during the first 4 weeks. HCV RNA was not detectable in any serum or liver sample and electron microscopy failed to reveal viral particles in liver tissue. In conclusion, we did not find Chacma baboons to be susceptible to infection with HCV, although we cannot deny that in an immunosuppressed liver transplant recipient, infection of a baboon xenograft might occur. Another animal model for HCV infection must be sought.

Animals↗
PubMed2001

Hepatitis B virus DNA in serum of healthy black African adults positive for hepatitis B surface antibody alone: possible association with recombination between genotypes A and D.

In some patients with chronic liver disease induced by hepatitis B virus, viral DNA is known to persist in low concentration in serum after seroconversion to hepatitis B surface antibody-positivity. This phenomenon has, however, not been documented in asymptomatic black African carriers of hepatitis B virus. Using nested amplification by the polymerase chain reaction, we detected low concentrations of hepatitis B virus DNA in the serum of 6 of 23 (26%) healthy black African adults with normal liver function and with hepatitis B virus surface antibody as the only serological marker of the virus. This finding offers one explanation for the earlier observation of integrated hepatitis B virus DNA in hepatocellular carcinomas in black Africans whose serum was positive for surface antibody alone. A number of genetic changes were found in the six isolates that might be responsible for evasion of the immune response and persistence of the virus. Isolated mutations were detected in the "a" determinant of the surface gene and in the encapsidation signal. In all five isolates sequenced in the core promoter, mutations were present in the upstream regulatory region. Recombination between genotypes A and D was present in three of the isolates, including both of those in which the entire genome was sequenced. This change in genotype also overlapped the amino end of the polymerase domain and may result in sufficiently low levels of replication to allow viral persistence. Topoisomerase 1 specific trinucleotides were concentrated in the vicinity of the recombination breakpoints.

Adult↗
PubMed2001

Expression of c-myc promoter binding protein (MBP-1), a novel eukaryotic repressor gene, in cirrhosis and human hepatocellular carcinoma.

We have examined the expression of c-myc and c-myc promoter binding protein (MBP-1), a novel eukaryotic repressor, in human hepatocellular carcinoma and cirrhosis by semiquantitative reverse transcription PCR amplification. Levels were normalized for glyceraldehyde-3-phosphate dehydrogenase messenger RNA and then compared between these two groups and to normal liver. We found that MBP-1 expression was significantly decreased in cirrhosis and c-myc and MBP-1 were even further diminished in hepatocellular carcinoma. There was no clear correlation between MBP-1 and c-myc messenger RNA levels. Our results therefore suggest that expression of MBP-1 and c-myc are decreased in a stepwise fashion in the presence of chronic liver disease and hepatocellular carcinoma in humans and that further study of the interactions of these two genes and their products is warranted to determine their role in human hepatocarcinogenesis.

Biomarkers, Tumor↗
PubMed2001

Characterization of proteinuria in asymptomatic family members and household contacts of children with hepatitis B virus-associated membranous nephropathy.

The biosocial background in which the hepatitis B virus (HBV) carrier state with membranous nephropathy (MN) develops was studied by evaluating HBV carriage and proteinuria among 195 family members and household contacts of 31 index HBV carrier children with MN. Unrelated individuals from the communities of these index cases who were negative for HBV served as controls (n = 123). HBV was determined by using third-generation enzyme-linked immunosorbent assay, slot-blot hybridization, and nested polymerase chain reaction. Patterns of proteinuria were determined by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis; immunoglobulin G and haptoglobulin were suggestive of MN. Seventy-two members (36.9%) of the study group (n = 195) were HBV carriers; 21 of these carriers (29.2%) had proteinuria. Twenty-eight members (41.2%) of the study group who were HBV negative (n = 68) and 26.8% of the controls showed proteinuria. This lack of association between HBV carriage and proteinuria remained when controlled for sex and family relationship. HBV was not protective against the development of proteinuria. Proteinuria suggestive of MN was strongly associated with an abnormal protein-creatinine ratio (P: = 0.001), but was not significantly different between subjects and controls (8.7% versus 6.5%; P: = 0.5). Genetic influences or environmental exposures in these subjects may be responsible for the proteinuria, suggesting underlying glomerular basement membrane damage. Discordance between the HBV carrier state and patterns of proteinuria in the study group suggest that HBV and MN may not be causally related or may reflect exceptional interaction between specifically vulnerable individuals and HBV.

Adolescent↗
PubMed2001

Sister Joseph's nodule in hepatocellular carcinoma.

We describe three black South African patients in whom hepatocellular carcinoma metastasized to the umbilicus. Sister Joseph's nodule has previously been reported in only two patients with this tumour. A number of routes for this spread are possible: malignant hepatocytes in the portal venous system may reach the umbilicus via a patent umbilical vein; the tumour may propagate directly along the ligamentum teres hepatis to the umbilicus; contiguous spread of the tumour to the umbilicus from anterior peritoneal tissue, either directly infiltrated by hepatocellular carcinoma or the site of metastatic nodules, may occur; embolization of malignant hepatocytes to the umbilicus might take place by way of its arterial blood supply; or hepatocellular carcinoma might reach the umbilicus as a result of retrograde lymphatic spread from para-aortic lymph nodes or from the anterior abdominal wall, to which the tumour has metastasized.

Abdominal Neoplasms↗
PubMed2001

Molecular analysis of hepatitis B virus genomes isolated from black African patients with fulminant hepatitis B.

To investigate further the possible role of mutant hepatitis B viruses in the pathogenesis of fulminant hepatitis B, the genomic sequence of hepatitis B virus isolates from 9 South African blacks with this disease, including 5 entire genomes, was analysed. Seven of the isolates were genotype A. The mutation most often reported in patients with fulminant hepatitis B, the G1896A precore stop-codon substitution, was, as expected, not present in the genotype A isolates with the exception of one in which it was accompanied by a compensatory C1858T substitution. G1896A was, however, present in the one genotype D isolate. No other precore-defective mutants were detected. The other mutation commonly found in patients with fulminant hepatitis B, the paired A1762T, G1764A substitution in the basic core promoter, was present in only one patient and G1764A in one other. The pre-surface initiation-codon mutation documented in a number of patients with fulminant hepatitis B was not found in our isolates. An 18-amino acid deletion present in the pre-surface region of one isolate has not previously been described in fulminant hepatitis B. Variations within the surface region were mainly genotype specific and not previously described. A relatively large number of mutations were present in the middle region of the core gene in those isolates without G1896A or A1762T, G1764A mutations, although the pattern was not consistent with those in published studies. Thus, as in other published series in which the entire genome of hepatitis B virus responsible for fulminant hepatitis was sequenced, we detected many mutations in different genes, but none was common to all the reported isolates.

Adolescent↗
PubMed2000

Susceptibility of chacma baboons (Papio ursinus orientalis) to infection by hepatitis B virus.

BACKGROUND: Because baboons are being considered as a source of xenografts for human liver transplantation in patients with hepatitis B virus- (HBV) induced cirrhosis to forestall infection of the graft by the virus, we undertook a study to ascertain if baboons are resistant to HBV infection. METHODS: Six chacma baboons were inoculated with serum containing HBV and were followed for 52 weeks to detect transmission of infection. RESULTS: Anti-HBc was detected in the serum of four baboons 16 weeks after inoculation. Virions, small spherical particles, and tubular forms were seen at this time in the serum of the one baboon studied by transmission electron microscopy. HBV DNA was detected by polymerase chain reaction in the serum of the same four baboons throughout the period of follow-up, as well as in liver tissue obtained after 52 weeks. The specificity of the DNA was confirmed by Southern hybridization. Nucleotide sequences showed complete sequence identity between the HBV DNA in each of the baboon sera and one of the two HBV genotypes inoculated. Serum transaminase levels tested at 4-weekly intervals were always normal and histological examination of liver tissue after 52 weeks showed no evidence of chronic hepatitis. Examination of squash preparations of liver tissue by electron microscopy in one baboon revealed core-like particles. CONCLUSIONS: Chacma baboons are susceptible to HBV infection and appear to develop a chronic carrier state. The use of xenografts from baboons should preferably be avoided, but if they are used again for HBV-infected patients it would be prudent to treat the patients as if they had received an organ from a human donor.

Animals↗
PubMed2000

p73 is up-regulated in a subset of hepatocellular carcinomas.

Loss of heterozygosity (LOH) at 1p36 occurs in a number of solid tumors including hepatocellular carcinoma (HCC). Recently, a novel gene, p73, has been identified at 1p36.33. p73 is structurally and functionally related to p53 located at 17p13.1, which is a target for inactivation in HCCs. p73 produces at least two splicing variants, p73alpha and beta, and a polymorphism in exon 2 results in two alleles, GC or AT. Initially, only the AT allele and p73alpha transcripts were identified in malignant cell lines, suggesting a role for these in the malignant phenotype. The aims of this study were to determine the extent of LOH at 1p36 and 17p13.1 in HCCs from Australia and South Africa, and to identify patterns of p73 mRNA and p73 and p53 protein expression. LOH at 1p36 was found in 8 of 25 Australian and 6 of 10 South African cases. p73 mRNA expression occurred in 8 HCCs, but not in nonmalignant liver tissue. Two of these 8 HCCs had LOH of 1p36. Both alpha and beta transcripts were observed in GC/GC homozygotes and GC/AT heterozygotes. No p73 protein expression was observed by immunohistochemistry in nonmalignant liver tissue or in HCC. p53 inactivation appeared to be associated with up-regulation of p73 expression, suggesting a compensatory role for p73 in this situation. The LOH at 1p36 implies a liver-specific tumor suppressor gene is in this region. However, the up-regulation of p73 mRNA suggests p73 is not the target of this loss.

Adult↗
PubMed2000

Hepatocellular cancer. A century of progress.

Although gratifying progress has been made during the 20th century, much remains to be achieved. The principal objective must be prevention of HCC. Prevention of HBV-related tumors is already feasible, and prevention of HCV-related and aflatoxin-induced tumors should soon become possible. Not all HCCs are yet accounted for causatively, and the remaining risk factors need to be identified. Until primary prevention can be accomplished, attention must also be directed to obtaining a complete understanding of the pathogenesis of HCC so that strategies for secondary and tertiary prevention can be formulated and instituted. Finally, the search for effective anticancer treatment must continue.

Carcinoma, Hepatocellular↗
PubMed2000

Transfusion-transmissible virus and hepatocellular carcinoma: a case-control study.

Although transfusion-transmissible virus (TTV) is often present in the serum of patients with acute and chronic non-A-C liver diseases, its hepatotropism, pathogenicity to the liver and hepatocarcinogenicity have not been proven. We used a case-control format to compare the prevalence of TTV infection among 148 southern African Blacks with hepatocellular carcinoma and 148 matched hospital-based controls, and to test for possible interactive effects between this virus and hepatitis B virus (HBV) and hepatitis C virus (HCV) in the development of the tumour. We also determined the prevalence of TTV in 988 blood donors in Gauteng province of South Africa. The presence of TTV DNA in serum samples was detected by using the polymerase chain reaction, Southern hybridization and nucleotide sequencing. Individuals infected with TTV did not have an increased risk of developing hepatocellular carcinoma (relative risk 1.1; 95% confidence limits 0.5-2.4). Moreover, co-infection with TTV did not further increase the risk of tumour development in patients chronically infected with HBV and/or HCV. TTV was present in the serum of 2.2% of blood donors: 4.0% in Black and 1.5% in White donors. We conclude that TTV is unrelated to the development of hepatocellular carcinoma in Black Africans.

Adolescent↗
PubMed1999

High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers.

The purpose of this study was to identify mutations in the basic core promoter and enhancer II region of the hepatitis B virus (HBV) that might cause the HBV e antigen (HBeAg)-negative phenotype and contribute to hepatocarcinogenesis in black African carriers of the virus. The basic core promoter/enhancer II overlaps with the X gene. HBV DNA from serum of 47 asymptomatic carriers and 50 patients with hepatocellular carcinoma and from 28 tumor and 10 nontumor liver tissues was amplified and sequenced directly. That part of the enhancer II region not overlapping the basic core promoter was completely conserved in all samples. Missense mutations at nucleotides 1809 and 1812 in the basic core promoter were found in 80% of all sequences and may represent wild-type sequence in Southern African isolates. Nucleotide and amino acid divergences were higher in the basic core promoter of hepatocellular carcinoma patients when compared with asymptomatic carriers (P <.0001). This applied particularly to the paired 1762 adenine to thymine (1762(T)) and 1764 guanine to adenine (1764(A)) missense mutations, the prevalence of which was 66% in patients with hepatocellular carcinoma compared with 11% in asymptomatic carriers (P <.0001). There was no association between the presence of 1762(T) 1764(A) and HBeAg negativity, although these mutations suppressed HBeAg titers in HBeAg-positive patients. Suppression of HBeAg expression as well as alteration of the amino acid sequence of the X protein may play a role in hepatocarcinogenesis.

Amino Acid Sequence↗
PubMed1999

The core promoter of hepatitis B virus.

The core promoter (CP) of hepatitis B virus (HBV) plays a central role in HBV replication and morphogenesis, directing the transcription of both species of 3.5 kb mRNA: pregenomic (pg) RNA and precore (pre-C) mRNA. The CP overlaps the 3' end of the X open-reading frame (ORF) and the 5' end of the pre-C/C ORF. The major functional elements of the CP are the upper regulatory region (URR) and the basic core promoter (BCP). The BCP is sufficient for accurate initiation of both pre-C mRNA and pgRNA transcription. It contains four AT-rich regions and the initiators for pre-C mRNA and pgRNA transcription. The upstream regulatory region consists of the negative regulatory element and the core upstream regulatory sequence. Co-operative interaction of various liver-enriched and ubiquitous transcription factors is necessary for liver-specific expression from the CP. These factors bind to the CP. Sequence conservation within the CP is crucial for maintaining active viral replication, and variation may contribute to the persistence of HBV within the host, leading to chronic infection and, ultimately, hepatocarcinogenesis. The most frequently described mutations within this region are an A to T transversion at position 1762 together with a G to A transition at position 1764. This double mutant is accompanied by a reduced level of hepatitis B e antigen (HBeAg) expression. Deletions, insertions and duplications occur within the CP.

Amino Acid Sequence↗
PubMed1999

HBV and proteinuria in relatives and contacts of children with hepatitis B virus-associated membranous nephropathy.

BACKGROUND: Hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) is an important cause of childhood nephrotic syndrome in regions endemic for the virus, but little is understood of the biosocial context in which the disease develops. We evaluated HBV status and proteinuria in family members and household contacts of index children with HBVMN to test the hypothesis that HBV carriage and asymptomatic proteinuria are closely linked and may be causally associated. METHODS: Thirty-one black children with biopsy-proven HBVMN were the index cases. One hundred and fifty-two family members and 43 black household contacts were the subjects of the study. We assessed HBV carrier status by testing for HBV antigens and antibodies using enzyme-linked immunosorbent assays (ELISA) and for HBV DNA by using slot-blot hybridization and the polymerase chain reaction. Sequencing of the precore region of HBV was done in a subset of both index cases and subjects. Proteinuria was assessed by measuring the urinary protein/creatinine ratio. RESULTS: Seventy-two (37%) of the 195 family members and household contacts were HBV carriers, and 53 (27%) had a protein/creatinine ratio greater than the physiological limit. The frequency of abnormal proteinuria was not significantly different in those with [22 out of 72 (30.5%)] or without [33 out of 104 (32%)] HBV carriage. This lack of association remained when carriers were classified into those who were HBsAg positive only and those with active viral replication (HBsAg and/or HBeAg and/or HBV DNA; P = 0.01). Family members were more predisposed to HBV carriage than household contacts, but abnormal proteinuria was present with equal frequency (P = 0.48). Age had a significant impact on proteinuria, with children less than five years being more likely to have abnormal proteinuria (P = 0.008). The prevalence of abnormal proteinuria in family members and household contacts of the index cases was more than that in community-based controls. The 10 index HBVMN cases and the 14 family members and household contacts who were tested all had HBV of genotype A. CONCLUSION: These results suggest that the family members and household contacts of children with HBVMN are at very high risk of HBV carriage; they also have asymptomatic proteinuria at a significantly higher rate than community-based controls. The HBV carrier status was not associated with proteinuria, a finding supported by peak prevalences of proteinuria in those under five years but no corresponding peak for HBV carriage. Proteinuria may indicate glomerular basement membrane dysfunction. Environmental and social factors may underpin development of these two covert disorders, but are insufficient to account for the index cases of HBVMN. The emergence of children with HBVMN from such households additionally depends on unidentified and possibly genetic factors.

Adolescent↗