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A C Paterson

Publications and source records attributed to A C Paterson.

At least 19 recordsLinked to original sources

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↗

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↗

Non-transferrin-bound iron and hepatic dysfunction in African dietary iron overload.

BACKGROUND: Circulating iron is normally bound to transferrin. Non-transferrin-bound iron (NTBI) has been described in most forms of iron overload, but has not been studied in African dietary iron overload. This abnormal iron fraction is probably toxic, but this has not been demonstrated. METHODS: High-pressure liquid chromatography was used to assay serum NTBI in 25 black African subjects with iron overload documented by liver biopsy and in 170 relatives and neighbours. Levels of NTBI were correlated with indirect measures of iron status and conventional liver function tests. RESULTS: Non-transferrin-bound iron (> 2 micromol/L) was present in 43 people, 22 of patients of whom underwent liver biopsy and 21 relatives and neighbours. All but four of these had evidence of iron overload on the basis of either liver biopsy or elevated transferrin and serum ferritin concentrations. Among all 195 subjects, the presence of NTBI in serum was independently related to elevations in alanine and aspartate aminotransferase activity and bilirubin concentration. This relationship between serum NTBI and hepatic dysfunction was confirmed in the subgroup of 25 subjects with iron overload documented by liver biopsy. Non-transferrin-bound iron correlated significantly with elevations in alanine and aspartate aminotransferase activities after adjustment for hepatic iron grades, inflammation and diet. CONCLUSIONS: Non-transferrin-bound iron was found to be commonly present in African patients with dietary iron overload and to correlate with transferrin saturation and serum ferritin concentration. The independent relationship between NTBI and elevated liver function tests suggests that it may be part of a pathway leading to hepatic injury.

Aspartate Aminotransferases↗

Measurements of iron status and survival in African iron overload.

INTRODUCTION: Dietary iron overload is common in southern Africa and there is a misconception that the condition is benign. Early descriptions of the condition relied on autopsy studies, and the use of indirect measurements of iron status to diagnose this form of iron overload has not been clarified. METHODS: The study involved 22 black subjects found to have iron overload on liver biopsy. Fourteen subjects presented to hospital with liver disease and were found to have iron overload on percutaneous liver biopsy. Eight subjects, drawn from a family study, underwent liver biopsy because of elevated serum ferritin concentrations suggestive of iron overload. Indirect measurements of iron status (transferrin saturation, serum ferritin) were performed on all subjects. Histological iron grade and hepatic iron concentration were used as direct measures of iron status. RESULTS: There were no significant differences in either direct or indirect measurements of iron status between the two groups. In 75% of these subjects the hepatic iron concentration was greater than 350 micrograms/g dry weight, an extreme elevation associated with a high risk of fibrosis and cirrhosis. Serum ferritin was elevated in all subjects and the transferrin saturation was greater than 60% in 93% of the subjects. Hepatomegaly was present in 20 of the 22 cases and there was only a moderate derangement in liver enzymes except for a tenfold increase in the median gamma-glutamyl transpeptidase concentration. There was a strong correlation between serum ferritin and hepatic iron concentrations (r = 0.71, P = 0.006). After a median follow-up of 19 months, 6 (26%) of the subjects had died. The risk of mortality correlated significantly with both the hepatic iron concentration and the serum ferritin concentration. CONCLUSIONS: Indirect measurements of iron status (serum ferritin concentration and transferrin saturation) are useful in the diagnosis of African dietary iron overload. When dietary iron overload becomes symptomatic it has a high mortality. Measures to prevent and treat this condition are needed.

Adult↗

Evidence of genetic transmission in African iron overload.

Iron overload in Africa was previously regarded as purely due to excessive iron in traditional beer, but we recently found evidence that transferrin saturation and unsaturated iron binding capacity may be influenced by an interaction between dietary iron content and a gene distinct from any HLA-linked locus. To determine if serum ferritin follows a genetic pattern and to confirm our previous observations, we studied an additional 351 Zimbabweans and South Africans from 45 families ranging in size from two to 54 members. Iron status was characterized with repeated morning measurements of serum ferritin, transferrin saturation, and unsaturated iron binding capacity after supplementation with vitamin C. For each measure of iron status, segregation analysis was consistent with an interaction between a postulated iron-loading gene and dietary iron content (P < .01). In the most likely model, transferrin saturation is 75% and serum ferritin is 985 micrograms/L in a 40-year-old male heterozygote with an estimated beer consumption of 10,000 L, whereas the saturation is 36% and serum ferritin is 233 micrograms/L in an unaffected individual with identical age, sex, and beer consumption. This segregation analysis provides further evidence for a genetic influence on iron overload in Africans.

Adult↗

Dietary iron overload as a risk factor for hepatocellular carcinoma in Black Africans.

Although the iron-loading disease, hereditary hemochromatosis, has a strong causal association with hepatocellular carcinoma (HCC), the carcinogenic potential of dietary iron overload in Black Africans is not known. We investigated this potential by evaluating iron status, alcohol consumption, markers for hepatitis B (HBV) and C virus (HCV) infections, and exposure to dietary aflatoxin B1 in 24 rural patients with this tumor, 48 race-, sex-, and age-matched hospital-based controls, and 75 related or unrelated close family members of the cancer patients. Iron overload was defined as a raised serum ferritin concentration in combination with a transferrin saturation > or = 60%, and was confirmed histologically when possible. Among 24 patients and 48 hospital controls, the risk of developing HCC in the iron-loaded subjects was 10.6 (95% confidence limits of 1.5 and 76.8) relative to individuals with normal iron status, after adjusting for alcohol consumption, chronic HBV and HBC infections, and exposure to aflatoxin B1. The risk of HCC in subjects with HBV infection was 33.2 (7.2, 153.4) (odds ratio [95% confidence limits]), HCV infection 6.4 (0.3, 133.5), and alcohol consumption 2.0 (0.5, 8.2). Aflatoxin B1 exposure did not appear to increase the risk of HCC. The population attributable risk of iron overload in the development of HCC was estimated to be 29%. Among 20 cancer patients and 75 family members, the risk of developing HCC with iron overload was 4.1 (0.5, 32.2). We conclude that dietary iron overload may contribute to the development of HCC in Black Africans.

Adolescent↗

A comparative study on hepatocellular carcinoma between South Africans and Japanese from the viewpoint of nuclear DNA content.

Nuclear deoxyribonucleic acid (DNA) content of hepatocellular carcinoma (HCC) in 41 South African and 47 Japanese patients at autopsy was analysed by dual-wavelength microspectrophotometry. The DNA distribution patterns were classified as type I, II, III or IV and as low ploidy (types I, II) or high ploidy (types III, IV), according to the degree of dispersion. We found a significantly higher incidence of high ploidy in South African HCC than in Japanese HCC. Moreover, type IV was significantly more frequent among South Africans than among the Japanese. These findings demonstrate that large differences in biological characteristics and clinical behaviour of HCC between South Africa and Japan may reflect differences in DNA distribution patterns which we observed between these two races.

Adolescent↗

Association between human papillomavirus and carcinoma of the oesophagus in South African blacks. A histochemical and immunohistochemical study.

Twenty specimens from patients who had undergone oesophagectomy for invasive squamous carcinoma of the oesophagus were examined for morphological evidence of human papillomavirus infection; it was found in 13 specimens. Nineteen specimens showed focal epithelial hyperplasia of the non-neoplastic mucosa. The material was also submitted to immunoperoxidase and modified Feulgen staining to detect viral antigen. Positive Feulgen staining was detected in the superficial layers of the squamous mucosa in 15 specimens, while immunoperoxidase was entirely negative. This demonstrates a possible association between human papillomavirus and oesophageal carcinoma and that the modified Feulgen method may be more sensitive than immunoperoxidase for the detection of viral antigen. Electron microscopy and molecular hybridisation would have to be used for confirmation.

Adult↗

Liver cell dysplasia accompanying hepatocellular carcinoma in southern Africa. Differences between urban and rural populations.

Liver cell dysplasia (LCD) has been recognised for many years in association with hepatocellular carcinoma (HCC). The presence of LCD relates to cirrhosis, particularly macronodular, as well as HBsAg positivity in many countries. These relationships have not previously been recognised in southern Africa. This study of LCD in 160 rural and urban black patients with proven HCC records a significant difference between the prevalence of dysplasia in rural HBsAg-positive and -negative cases: 75.6% in HBsAg+ individuals vs. 29.4% of those negative for HBsAg (P less than 0.01). Furthermore a significant relationship is reported between dysplasia and macronodular cirrhosis, LCD being observed in 62.9% of those with macronodular cirrhosis vs. 29.5% of non-cirrhotics (P less than 0.001). In addition there was evidence for a relationship between severity of dysplasia and domicile (rural greater than urban), age (being more extensive in younger patients), and ongoing viral replication (82.3% of patients showing the highest grade of dysplasia were found to be serum HBeAg+ and/or tissue HBcAg+ cf. 3.7% with absent or low-grade dysplasia). It is apparent that in southern Africa the presence of dysplasia in HBsAg+ individuals implies that HCC should be actively excluded in these patients and that they should thereafter be carefully monitored for the development of a tumour.

Adult↗

HLA expression in human hepatocellular carcinoma.

This study examines the expression of MHC class I and II antigens and their related invariant chains in 70 cases of human hepatocellular carcinoma (HCC), using monoclonal (Mabs) and polyclonal antibodies. In comparison with normal hepatocytes, the majority (94.3%) of HCCs show enhancement or acquisition of HLA-A, B, C in either a cytoplasmic or membranous distribution, with staining being uniformly distributed throughout the specimen. HLA-A, B, C was accompanied by beta 2-microglobulin expression in all but two cases. Although 44.9% of specimens showed HLA-DR expression, positively staining tumour cells were often sparse and heterogeneously distributed. By contrast, the invariant (I) chain, present in 47.1% of cases, was frequently intensively stained and extensive in distribution. HLA-DR staining was usually cytoplasmic although two cases showed faint membranous enhancement. In addition to HLA-DR and I-chain, two cases also showed HLA-DQ staining. Display of MHC antigens was not related to tumour differentiation or size of the lesion (resected vs. advanced tumours). It is possible that the acquisition of class I antigens by the majority of HCCs may influence tumour behaviour.

Carcinoma, Hepatocellular↗

Transferrin receptor expression in human hepatocellular carcinoma: an immunohistochemical study of 34 cases.

Using a panel of five monoclonal anti-transferrin receptor antibodies, we investigated the transferrin receptor expression in 34 human hepatocellular carcinomas of Belgian (n = 6), Italian (n = 7) and South African (n = 21) origin. For comparison the tumours were also stained with the monoclonal antibody BK 19.9, recognizing an antigen biochemically similar to the transferrin receptor, and with a monoclonal antibody against the epidermal growth factor receptor. Hepatocellular carcinomas express large amounts of transferrin receptors as demonstrated by the intense transferrin receptor immunostaining in 33/34 cases. Differences in staining pattern between and within the tumours were not related to the degree of tumour differentiation, nor to the origin or race of the patient. In 15 cases which included non-tumoural tissue, the tumour was more intensely stained than the surrounding liver parenchyma. The BK 19.9 immunoreactivity was generally weaker and mainly involved stromal cells, except in three cases where an intense staining of the tumour cells was seen. The epidermal growth factor receptor staining was also weaker and only in four cases was the immunoreactivity of the tumour stronger than the surrounding parenchyma. Demonstration of the transferrin receptor may be useful for the detection of malignant foci in liver biopsies. This may be of particular interest in the histological investigation of minute hepatocellular carcinomas.

Biopsy↗

Hepatocellular carcinoma in urban born blacks: frequency and relation to hepatitis B virus infection.

Chronic hepatitis B virus infection is far less common in urban born than in rural born southern African blacks, who also have a high incidence of hepatocellular carcinoma. A case-control study was carried out to determine the relative frequency of hepatocellular carcinoma and its relation to hepatitis B virus infection in urban born blacks. Three hundred and ninety two black patients with hepatocellular carcinoma and matched controls seen at two city hospitals were classified by questioning as urban born or rural born. The ratio of rural born to urban born blacks among the controls was 1.1:1.0 (207/185), whereas in the patients with cancer the ratio was 4.8:1.0 (324/68) (p less than 0.0001). Analysis of the prevalence of hepatitis B markers in 62 urban born and matched rural born blacks with hepatocellular carcinoma showed no differences in the frequency of current or past hepatitis B virus infection. It is concluded that urban born blacks are less likely than rural born blacks to develop hepatocellular carcinoma, but when they do the tumour is equally likely to be related to infection with hepatitis B virus. The findings lend further support to an important role for chronic hepatitis B virus infection in the aetiology of hepatocellular carcinoma.

Adolescent↗

Esophagitis in a population at risk for esophageal carcinoma.

A previously unreported high incidence of endoscopically identifiable, diffuse, largely nonulcerative esophagitis, is described in a selected population of Southern African blacks at risk of cancer of the esophagus. This is comparable with findings in similar groups in Iran and China. The incidence of dysplasia and "early" cancer is still undefined in South Africa.

Adolescent↗

Prevalence of hepatitis B virus infection among black children in Soweto.

Roughly 15% of black children in rural areas of southern Africa are carriers of the hepatitis B virus. The purpose of the present study was to determine the prevalence of chronic hepatitis B virus infection among urban black children born and growing up in Soweto. A total of 2364 children were studied, ranging in age from 3 to 19 years, and of these, 1319 (56%) were girls. The children were drawn from the highest and the lowest socioeconomic classes. Serum samples were tested for all hepatitis B virus markers as well as IgG antibody against hepatitis A virus. HBsAg was detected in 23 (0.97%) of the children, anti-HBc and anti-HBs together in 155 (6.6%), anti-HBc alone in 17 (0.7%), and anti-HBs alone in 72 (3%). Of the 2364 children, 2097 (88.5%) were negative for all hepatitis B virus markers. IgG antibody to hepatitis A virus was present in 175 (97%) of a sample of 179 children. There was no difference in prevalence of hepatitis B virus markers between children from the upper and lower socioeconomic classes. HBsAg was more common in boys (16 out of 1043 (1.5%) than girls (seven out of 1321 (0.57%), and the prevalence of all hepatitis B virus markers increased with age. The youngest carrier of hepatitis B virus was 7 years old. The remarkable difference in the hepatitis B virus carrier rate between urban and rural black children offers a unique opportunity to investigate the favourable influences operating in an urban environment to limit the prevalence of hepatitis B virus infection.

Adolescent↗

Recombinant leucocyte interferon treatment of chronic hepatitis B. An analysis of two therapeutic trials.

We have investigated the efficacy of recombinant alpha-interferon treatment of chronic hepatitis B virus (HBV) infection in two therapeutic trials. Forty-four patients positive for HBsAg, HBeAg, DNA polymerase and HBV-DNA were studied. Fourteen carriers were treated in the first trial with doses ranging from 18 to 50 million units (mu)/m2 3 times per week. Six of 14 treated carriers (43%) have a sustained loss of HBeAg, HBV-DNA and DNA polymerase. Four lost HBsAg (29%). Two of 11 (18%) untreated carriers lost HBeAg, but none lost HBsAg (P = 0.05). Nineteen patients were entered in a second trial to assess dose response. Fourteen were treated with doses ranging from 2.5 to 10 mu/m2. Five patients were untreated. Two treated patients seroconverted to anti-HBe, and a third cleared HBsAg and seroconverted to anti-HBs. None of the controls was anti-HBe-positive. Thus 9/28 (32%) carriers have lost replicating HBV versus 2/16 (13%) of untreated patients. Elevated pretreatment serum ALT concentrations and severe chronic active hepatitis were associated with inhibition of viral replication in treated patients suggesting that seroconversion may require an appropriate host response. The efficacy of recombinant interferon is restricted, but it may be of benefit in a proportion of carriers.

Adult↗

Detection of alpha-foetoprotein messenger RNA in human hepatocellular carcinoma and hepatoblastoma tissue.

Alpha-foetoprotein (AFP) synthesis, although repressed in normal adults, is increased in the majority of patients with hepatocellular carcinoma (HCC). We have investigated whether active transcription of the AFP gene may explain raised serum AFP concentrations in patients with HCC and hepatoblastoma by assaying human tumour and non-neoplastic tissue by molecular hybridization for the presence of mRNA encoding AFP. Ten operative HCC and six autopsy HCC specimens, two HCC cell lines, and one hepatoblastoma specimen were examined. Total cellular RNA and poly-(A)+ RNA were extracted and AFP mRNA sequences sought by dot-blot and Northern blot hybridisation to a human cDNA AFP probe. Cellular AFP was localised by avidin-biotin staining. AFP mRNA was detected in 8/10 operative specimens, as well as PLC/PRF/5 nude mouse tumours. Weaker hybridization was detected in 4/6 autopsy specimens. Signals of comparable intensity to that in operative tumours were detected in non-neoplastic tissue of 6 patients. AFP mRNA from nude mouse tumours migrated as a 20S discrete band on agarose gel electrophoresis, whereas a more complex hybridization pattern was evident in human tumours. Positive cytoplasmic immuno-staining for AFP was observed in 4 tumours and 2 corresponding non-neoplastic specimens and in a HCC cell line. In non-neoplastic liver, AFP was localised in cells that appeared dysplastic. Thus steady-state levels of AFP mRNA are detectable in human HCC tissue and surrounding non-neoplastic liver. These findings may prove pertinent to an understanding of the genetic expression of AFP in malignant hepatocytes, and the sequence of events leading to uncontrolled cellular proliferation.

Carcinoma, Hepatocellular↗