Primary biliary cirrhosis.
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Autoimmune Diseases↗
Biomedical subjects
M F Bassendine
Publications and source records attributed to M F Bassendine.
Immunogenicity of biliary epithelium: study of the adhesive interaction with lymphocytes.
BACKGROUND & AIMS: Intrahepatic bile ducts express a range of lymphocyte adhesion molecules during episodes of inflammation. This may contribute to the susceptibility of biliary epithelium to immunologic damage during liver allograft rejection, graft-versus-host disease, and primary biliary cirrhosis. However, no previous study has shown that these adhesion molecules are functional. The aim of this study was to define the molecular basis of lymphoepithelial interactions within the intrahepatic bile ducts. METHODS: Human intrahepatic biliary epithelial cells (HIBECs) were cultured, and their interaction with resting and activated lymphocytes was studied using a flow-cytometric assay that allowed characterization of the adherent cells and functional investigation of individual adhesive interactions. The capacity of adherent cytotoxic lymphoid cells to damage HIBEC was studied using a standard 51Cr release assay. RESULTS: Allogeneic lymphocytes were bound by HIBECs; this adherence was increased by activation of either participating cell type. Cells with cytotoxic capacity were bound preferentially. At least 50% of the overall adhesion was dependent on lymphocyte function-associated antigen 1. Cytotoxicity assays showed that HIBECs were susceptible to lysis by lymphokine-activated natural killer cells. CONCLUSIONS: This study shows that the adhesion molecules expressed by HIBECs are functional and necessary for the activity of cytotoxic effector lymphocytes.
Bile Ducts, Intrahepatic↗
Biochemistry and autoimmune response to the 2-oxoacid dehydrogenase complexes in primary biliary cirrhosis.
Pyruvate dehydrogenase complex (PDC), 2-oxo-glutarate dehydrogenase complex (OGDC), and the branched-chain 2-oxoacid dehydrogenase complex (BCOADC) constitute the 2-oxoacid dehydrogenase family of multienzyme complexes. These complexes, which are larger than ribosomes and which consist of multiple copies of E1, E2, and E3 subunits together with regulatory kinases and phosphatases and, in the case of PDC, an E3-binding protein (protein X), each play an important role in oxidative metabolism in mitochondria. Primary biliary cirrhosis (PBC) is associated with a high incidence of autoantibodies directed at mitochondrial autoantigens (the antimito-chondrial antibodies), identified as the E2 components of PDC, OGDC, and BCOADC, together with protein X and the E1 alpha and E1 beta subunits of PDC. The dominant B-cell autoepitope in PBC has been identified as the inner lipoic acid binding domain of PDC-E2, with the lipoic acid co-factor, which plays a critical role in E2 enzymatic activity, playing a role in autoantibody binding to antigen. Autoreactive CD4+ T cells specific for human PDC-E2 are also present in both the peripheral blood and liver mononuclear cell infiltrates of PBC patients. The mechanism of break-down of B-cell and T-cell self-tolerance to these ubiquitous mitochondrial antigens in such an organ-specific manner remains unclear. The apparent importance of autoreactive responses to these self-antigens does, however, raise the possibility that antigen-specific immunotherapy may offer a novel route to therapy in PBC.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Risk factors and medical follow-up of drug users tested for hepatitis C--can the risk of transmission be reduced?
Of 1728 patients attending a regional drug and alcohol clinic, 202 were considered at risk of hepatitis C virus (HCV). Forty-nine per cent (99/202) agreed to testing-67% (67) were HCV antibody positive. Age and a history of needle sharing was the significant factor associated with positive HCV status. Patients on methadone maintenance medication were more-likely to have been HCV positive, but significantly (p = 0.005) less likely to have shared needles in the previous year. Seventy-three per cent (49/67) attended for follow-up at a "liver clinic". Fifty per cent were infected with genotype 1a. Eighteen patients were biopsied and all were abnormal, ranging from mild hepatitis to severe fibrotic hepatitis. Attendance for medical follow-up was poor, which emphasizes the importance of preventative measures such as methadone maintenance programmes for reducing the spread of HCV.
Journal Article↗
Autoimmune hepatitis in older patients.
AIM: autoimmune hepatitis (AIH) is thought to present rarely in old people. The aims of the present study were to (i) review individuals diagnosed clinically as having AIH presenting over or under 65 years of age at Freeman Hospital, Newcastle, from 1979 to 1993 and (ii) compare diagnostic and histological scores, treatment and outcome, and hence provide a useful profile of the disease in older patients. METHODS: 310 individuals with a histological diagnosis of chronic hepatitis were identified, and review of the medical notes of 286 revealed 54 with a diagnosis of AIH. Of these, 12 (22%) were > or =65 years of age at presentation. RESULTS: at presentation, the mean diagnostic score (according to the diagnostic scoring system devised by an international panel; maximum score, 17) of the whole group was 11.5 (SD 3.5) and the mean score for those > or =65 years was 9 (SD 3). The mean histological grade (intensity of necro-inflammatory activity; maximum, 18) for the elderly group was 6 (SD 2) compared with 4.5 (SD 0.5) for the whole group. Despite this, 42% of the elderly sufferers had received no immunosuppressive therapy (versus 12% of the younger group). At follow-up, 26% in both groups had developed cirrhosis. None of the elderly group (but 7% of the younger group) had died from complications of chronic liver disease. CONCLUSION: we present data on 12 patients presenting at 65 years and over with AIH. In elderly individuals diagnosis may be more difficult, and treatment appears often to have been withheld. Despite this, and the more severe initial histological grade, the prognosis appeared no worse than in younger, usually correctly treated, patients.
Aged↗
Relationship between acetylator status, smoking, and diet and colorectal cancer risk in the north-east of England.
Some previous studies have suggested that the fast phenotype of the N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer because of greater activation of dietary heterocyclic amines, particularly in individuals who also consume well-done red meat, but other studies have not supported this. We describe a large case-control study examining the interaction between dietary, smoking and drinking habits, and acetylation genotype in relation to susceptibility to colorectal cancer. One-hundred-and-seventy-four incident cases and 174 matched controls were recruited. Genotyping for polymorphisms in NAT2 was performed using a method that detects >95% of slow alleles and data on personal habits were collected using a standardized questionnaire. We found no difference in the frequency of the fast acetylator genotype between cases and controls [odds ratio = 0.95 (95% CI 0.61-1.49)], and analysis by sex, age and site also revealed no difference in acetylator genotype. There was, however, considerable heterogeneity in dietary risk factors between fast and slow acetylators. Analysis by acetylator type shows that recent smoking was more frequent in slow acetylator cases than matched controls [OR = 2.31 (1.16-4.6)] and that heavy alcohol consumption was also more frequent in the slow acetylator cases than controls [OR = 2.5 (1.02-7.29)]. In contrast, frequent fried meat intake was seen more frequently in fast acetylator cases than matched controls [OR = 6.0 (1.34-55)]. The odds ratio for the combination of fast acetylator status and frequent fried meat consumption in cases was 6.04 (1.6-26). Our study suggests that there may be different risk factors for colorectal cancer in slow and fast acetylators, and reveals a new observation that slow acetylators may be at risk of colon cancer from smoking. In our community, the overall effect of acetylator status on colorectal cancer risk is neutral.
Acetylation↗
The prevalence of hereditary haemochromatosis in a diabetic population.
Hereditary haemochromatosis is an under-diagnosed and treatable cause of chronic liver disease. Its prevalence indicates that selective population screening may be worthwhile, but opinion differs as to whether diabetic patients constitute such a group. We studied 727 patients attending a teaching hospital diabetic clinic. On first testing, 7.4% had abnormally high iron indices, but only 3% remained abnormal on retesting. Of these patients, those at high risk were offered liver biopsy for histological assessment and iron assay. Only one had hereditary haemochromatosis, but all had abnormal liver histology--largely steatosis but some with fibrosis. These findings raise questions regarding the true prevalence of this disorder in North-East England, do not indicate that targeted screening of diabetic patients is worthwhile, and incidentally highlight the potential importance of diabetes as a cause of liver disease.
Adult↗
Outcome of post-transfusion hepatitis C: disease severity in blood-component recipients and their implicated donors.
The UK 'Look-back Program' identifies recipients of blood products from hepatitis C antibody (anti-HCV) positive donors. Of 60 such recipients tested by the Newcastle Transfusion Service, 28(46.7%) were anti-HCV-negative, 25(41.7%) were anti-HCV-positive, and seven (11.6%) had equivocal serology. We studied 29 anti-HCV-positive/indeterminate recipients and eight of their implicated donors, using serial liver function tests (LFTs), liver histology when clinically indicated, HCV RNA and serotyping. Presumed resolved hepatitis C, with persistently normal LFTs and negative HCV RNA, was found in 28%, of whom 63% had indeterminate anti-HCV by RIBA (1 band of 4 detected on third-generation recombinant immunoblot assay). Resolved hepatitis C was significantly more common in women (p < 0.05) and tended to be associated with younger age at transfusion. There was complete concordance in serotype between donor-recipient pairs. There was no correlation in disease severity between recipients and their implicated donors, nor between recipients from the same donor. A history of alcohol consumption above recommended 'safe' limits (median 30 units) was associated with more severe histological disease (p < 0.01). Host factors, including gender and alcohol consumption, may be important in determining the wide variability in outcome of post-transfusion hepatitis C.
Adolescent↗
Transjugular intrahepatic portosystemic shunt: a limited role in refractory ascites.
OBJECTIVE: To evaluate the role of the transjugular intrahepatic portosystemic shunt (TIPS) in the management of patients with refractory ascites. DESIGN: A retrospective study of 25 consecutive patients for whom refractory ascites was the primary indication for TIPS insertion. SETTING: Regional liver unit at Freeman Hospital, Newcastle upon Tyne, UK. PARTICIPANTS AND INTERVENTIONS: Twelve male and 13 female patients with a mean age of 58 years and mean Child-Pugh score of 10, treated with TIPS for refractory ascites between July 1992 and September 1995. MAIN OUTCOME MEASURES: Effect of TIPS on mortality, ascites and hospital admission rate. RESULTS: TIPS was successfully placed in all patients with a 59% mean reduction in portosystemic pressure gradient. Response rate was 68%, 48% and 33% at 1, 3 and 12 months, respectively. Mortality was 48% at 3 months and 67% at 12 months, being higher in those patients older than 60, those with renal impairment and those with higher Child-Pugh score. Amongst nine patients surviving long term (> 12 months) the mean time spent in hospital in the 3 months before TIPS was 35 days and in the year following TIPS 30 days. Patients who died (16 in total) spent a mean of 19 days in hospital before TIPS, 10 never leaving hospital, and 6 who were discharged spent a mean of 19 days post procedure in hospital (mean survival 84 days). CONCLUSION: TIPS has a limited role in the management of patients with refractory ascites. It is not an appropriate treatment where patients are older than 60, have renal impairment (creatinine > 200 mumol/l) or have a Child-Pugh score greater than 10.
Ascites↗
T cell responses to tuberculin purified protein derivative in primary biliary cirrhosis: evidence for defective T cell function.
BACKGROUND: Primary biliary cirrhosis (PBC) has an autoimmune aetiology, although little is known regarding the mechanisms of breakdown of self tolerance. One postulated mechanism of control of self tolerance is through interacting T cell subsets, a phenomenon explored in this study. AIMS: To characterise and compare T cell subset responses to an antigen (tuberculin purified protein derivative derived from mycobacteria) in PBC patients and controls. Cross reactive responses to mycobacteria have recently been implicated in the aetiology of PBC. SUBJECTS: 58 PBC patients, 25 normal controls, and 34 chronic liver disease controls. METHODS: Responses to antigen were measured in terms of primary T cell proliferation and cytokine secretion (by ELISA). Responding cells were phenotyped by FACS analysis. RESULTS: Similar CD4+ T cell proliferative responses were seen in PBC patients (mean (SD) stimulation index (SI) 22.6 (27.2), 42 of 58 (72.4%) positive response), normal controls (46.5 (88.0), 17 of 25 (68%) positive), and chronic liver disease controls (24.8 (49.8), 27 of 34 (79.4%) positive)). Secretion of both interferon gamma and IL10 was significantly lower in PBC patients than controls (IFN gamma: PBC 822.7 (1100) pg/ml, controls 2929 (3402) pg/ml, p < 0.05: IL10: PBC 11.1 (15.6) pg/ml, controls 34.7 (63.4) pg/ml, p < 0.05). CONCLUSIONS: In PBC unimpaired T cell proliferation is seen with reduced secretion of both Th-1 (interferon gamma) and Th-2 type (IL10) cytokines. These findings may result from differential subset responses and may help explain the defects of functional immunity seen in PBC.
Antigens, Bacterial↗
A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage.
BACKGROUND: Few studies have compared vasoactive drugs with endoscopic sclerotherapy in the control of acute variceal haemorrhage. Octreotide is widely used for this purpose, but its value remains undetermined. AIMS: To compare octreotide with endoscopic sclerotherapy for acute variceal haemorrhage. PATIENTS: Consecutive patients with acute variceal haemorrhage. METHODS: Patients were randomised at endoscopy to receive either a 48 hour intravenous infusion of 50 pg/h octreotide (n = 73), or emergency sclerotherapy (n = 77). RESULTS: Overall control of bleeding and mortality was not significantly different between octreotide (85%, 62 patients) and sclerotherapy (82%, 63 patients) over the 48 hour trial period (relative risk of rebleeding 0.83; 95% confidence interval (CI) 0.38 to 1.82), irrespective of Child's grading or active bleeding at endoscopy. One major complication was observed in the sclerotherapy group (aspiration) and two in the octreotide group (pulmonary oedema, severe paralytic ileus). During 60 days of follow up there was an overall trend towards an increased mortality in the octreotide group which was not statistically significant (relative risk of dying at 60 days 1.91, 95% CI 0.97 to 3.78, p = 0.06). CONCLUSIONS: The results of this study indicate that intravenous octreotide is as effective as injection sclerotherapy in the control of acute variceal bleeding, but further controlled trials are necessary to evaluate the safety of this treatment.
Acute Disease↗
Natural history of early primary biliary cirrhosis.
BACKGROUND: In 1986, we reported a group of 29 patients who were positive in serum for antimitochondrial antibody (AMA), the disease-specific marker for primary biliary cirrhosis (PBC), but who had normal liver function test results and no symptoms of liver disease. However, liver histology was diagnostic or compatible with PBC in 24 patients and normal in only two. The aims of this 10-year follow-up study were to establish whether patients with AMA have very early PBC, to assess the outlook for such patients, and to follow the progression of the disease. METHODS: All patients were assessed every year at our PBC clinic: records were reviewed, cause of death verified when applicable, and current clinical and biochemical data collected, including repeat liver histology as indicated. Serum samples from the original study were located. Original and follow-up serum samples were tested by ELISA for E2 components of pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex. FINDINGS: Five patients died during follow-up; no deaths were attributable to liver disease. Median follow-up of patients who survived was 17.8 years (range 11.0-23.9) from first-detected AMA to the last follow-up review. Overall, 22 (76%) developed symptoms of PBC and 24 (83%) had liver function tests persistently showing cholestasis. Repeat liver biopsy samples were obtained from ten patients; among these patients PBC progressed from Scheuer grade 1 to grade 2 in two and from grade 1 to grade 3 in two. No patient developed clinically apparent cirrhosis. ELISA of baseline serum samples from 27 patients was positive in 21, all of whom had original liver histology compatible with or diagnostic of PBC. Of the six patients who tested negative, only one had an original liver biopsy sample that was compatible with PBC. INTERPRETATION: This study confirms that before the advent of any clinical or biomedical indications, individuals positive for AMA do have PBC. This finding extends the natural history of PBC back in some cases for many years. What determines the eventual progression to biochemically and clinically apparent disease is not yet understood. During our study no patient developed clinically apparent portal hypertension or cirrhosis. Thus, although the finding of a solitary persistently raised AMA is confirmation of a diagnosis of PBC, patients with AMA but no other signs or symptoms of PBC seem to have slow progression of the disease.
Adult↗
Development of a flow cytometric assay to quantify lymphocyte adhesion to cytokine-stimulated human endothelial and biliary epithelial cells.
The adhesive interaction between T lymphocytes and parenchymal cells is of importance for many processes of the cellular immune response. This adhesion is regulated by the activation status of the T cell and by cytokines in the microenvironment which can alter adhesion molecule expression by endothelial and epithelial cells. In this study results from an isotopic adhesion assay were compared with those from a flow cytometric assay in order to determine which was most appropriate for the investigation of lymphocyte adhesion to human umbilical vein endothelial cells (HUVEC) and intrahepatic biliary epithelial cells (HIBEC). Treatment of both these cell types with the proinflammatory cytokines interferon-gamma (IFN-gamma) or tumour necrosis factor-alpha (TNF-alpha) significantly upregulated expression of intercellular adhesion molecule-1 (ICAM-1). Treatment with TNF-alpha also induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1). The isotopic assay demonstrated increased adhesion of lymphoblasts to HUVEC which had been stimulated with cytokines for 15 h but failed to detect major changes in adhesion following 72 h of cytokine treatment of HUVEC or HIBEC. However, the flow cytometric assay reproducibly demonstrated increased adhesion following cytokine treatment for both these time periods; these increases corresponded with the changes in adhesion molecule expression by cytokine-stimulated HUVEC and HIBEC targets. The differences in apparent adhesion measured by the two assays after cytokine stimulation for 72 h may be explained by cytokine-induced changes in the morphology and confluency of cultured cells. Results of the isotopic assay are proportional to the total number of lymphoid cells bound by the cultured target cells and will be distorted by changes in effective target cell area. The flow cytometric assay measures the mean number of lymphoid cells bound by each target cell and is independent of the total binding area. It is concluded that the flow cytometric assay is more suitable than the isotopic technique for following time-dependent changes in the adhesion of leukocytes to cytokine-stimulated target cells.
Bile Ducts, Intrahepatic↗
Immunogenicity of biliary epithelium: investigation of antigen presentation to CD4+ T cells.
The intrahepatic biliary epithelium is susceptible to extensive T-cell-mediated damage during primary biliary cirrhosis, primary sclerosing cholangitis, and hepatic allograft rejection. During these processes, human intrahepatic biliary epithelial cells (HIBEC) become activated and express high levels of the lymphocyte adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and lymphocyte-associated antigen (LFA)-3, and of class II MHC antigens. It follows that activated HIBEC may also play a direct role in the activation of antigen-specific CD4+ T lymphocytes. The capacity of class II MHC antigen-expressing HIBEC to present antigen and induce specific proliferation of CD4+ T cells was examined in this study. Lines of purified HIBEC were activated by culture with the proinflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor a and were mixed in coculture with allogeneic CD4+ T cells. The result of interaction between these cells was assessed by measurement of lymphoproliferation and IL-2 production. Class II MHC antigen-expressing HIBEC failed to induce either lymphoproliferation or IL-2 production. However, both of these parameters of T-cell activation were positive in cocultures when a costimulation signal was delivered to T cells by adding bivalent anti-CD28 antibodies. The antigen-specific activation of these T cells was further enhanced by the addition of a cross-linking secondary antibody that caused CD28 receptor aggregation. The failure of cytokine-stimulated HIBEC to induce T-cell activation is consistent with the observation that HIBEC do not express the costimulatory CD28 ligands B7-1 or B7-2 at either mRNA or protein levels. It may be concluded that HIBEC are unlikely to play a direct role in activation of antigen-specific CD4+ T lymphocytes within the inflamed liver.
Antibodies, Monoclonal↗
Hepatic allograft rejection: regulation of the immunogenicity of human intrahepatic biliary epithelial cells.
Intrahepatic biliary epithelial cells were immunomagnetically purified from specimens of disaggregated human liver and were propagated in vitro. After three passes in culture, the cells were shown to be over 85% pure with contaminating leukocytes and endothelial cells constituting less than 2% of the population. Sensitive flow microfluorimetric analysis was performed after immunofluorescence labeling to quantify expression of both class 1 and class II major histocompatibility (MHC) antigens and the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and lymphocyte function-associated antigen-3 (LFA-3). It was shown that resting human intrahepatic biliary epithelial cells (HIBEC) expressed class 1 MHC antigens, ICAM-1, and relatively low levels of LFA-3. Stimulation with tumour necrosis factor-alpha (TNF-alpha) upregulated expression of ICAM-1, whereas Interferon-gamma (IFN-gamma) and a combination of IFN-gamma and TNF-alpha upregulated class I MHC antigens and ICAM-1 and induced class II MHC molecules. The level of expression of MHC antigens and of ICAM-1 and LFA-3 after stimulation of HIBEC with combined IFN-gamma and TNF-alpha was comparable with the expression of these antigens by an Epstein-Barr virus-transformed B-cell line. The phenotypic similarity between cytokine-stimulated HIBEC and a known antigen presenting cell is consistent with a potential role for biliary epithelial cells in antigen presentation.
Bile Ducts↗
Characterisation of the DNA repair enzyme for O(6)-methylguanine in cirrhosis.
BACKGROUND/AIMS: The reason(s) why cirrhosis is a major risk factor for the development of hepatocellular carcinoma worldwide are largely unknown. In a previous preliminary study, we reported deficiency of the repair enzyme for the highly promutagenic and potentially carcinogenic DNA base lesion, O(6)-methylguanine, in cirrhotic human liver. The aims of the present study were: (i) to confirm this observation in an extended series of cirrhosis patients, using a new DNA repair enzyme assay approach, (ii) to characterise the enzyme, in particular to seek physicochemical differences between control and cirrhotic liver that might account for the enzyme defect in cirrhosis, and (iii) to examine the relationship between magnitude of DNA repair deficiency in cirrhotic liver and aetiology of cirrhosis or male sex, both of which are independent risk factors of hepatocellular carcinoma. METHODS: Tissue extracts containing DNA repair enzyme, O(6)-methylguanine-DNA methyltransferase, were prepared from liver biopsy samples from 41 patients with cirrhosis (10 viral (HBV and HCV), 17 alcohol and 14 autoimmune), 17 patients with non-cirrhotic diseased liver and 4 patients with histologically normal liver. Repair enzyme levels and electrophoretic profiles were both obtained using sodium dodecyl sulphate-polyacrylamide gel electrophoresis in conjunction with fluorography and densitometry. RESULTS: We have demonstrated the feasibility of both analysing and reproducibly measuring DNA repair enzyme in small liver biopsy samples using the gel electrophoresis/densitometry approach for enzyme assay. Using the new densitometric assay approach, levels of O(6)-methylguanine-DNA methyltransferase were found to be significantly lower in cirrhotic compared to non-cirrhotic liver, with very low values obtained for two individuals who were incidentally found to have small hepatocellular carcinomas at the time of liver transplantation. There were no significant differences in enzyme levels between patients with cirrhosis of different aetiology, and between male and female patients. Methyltransferase was found to be present in all liver extracts as a major 23.1 kDA protein, along with other less abundant enzyme forms of both slightly higher and lower molecular weight; there were no obvious differences in size and relative abundance of these enzyme forms between liver samples from any of the patient and control groups. Our findings of enzyme instability and multiple forms led us to examine methyltransferase's amino acid sequence for the presence of primary structure motifs indicative of targeted degradation of the enzyme by intracellular proteases. We have identified a eukaryotic thiol protease active site motif and two cyclin-like "destruction box" motifs in the N-terminal half of the enzyme. CONCLUSIONS: Our findings provide further evidence suggesting that deficiency in the ability to repair O(6)-methylguanine-DNA underlies the increased risk of hepatocellular carcinoma seen in patients with cirrhosis. The degree of DNA repair deficiency not varying between cirrhotic patients subgrouped according to other risk factors for hepatocellular carcinoma, suggests that DNA repair deficiency is only one of several contributory factors in liver carcinogenesis. The presence in methyltransferase of thiol protease active site and "destruction box" motifs may be of relevance to observed repair enzyme instability and presence of multiple enzyme forms in human liver extracts.
Amino Acid Sequence↗
Hepatitis C virus density heterogeneity and viral titre in acute and chronic infection: a comparison of immunodeficient and immunocompetent patients.
BACKGROUND: Heterogeneities in the buoyant density of hepatitis C virus RNA have been reported in different groups of patients, and have been attributed to differential binding of viral particles to beta-lipoproteins and IgG, and the presence of hepatitis C virus nucleocapsids in circulation. It may be that hepatitis C virus density heterogeneity correlates with the severity of liver disease, hepatitis C virus RNA titre, and the immunocompetence of the patient. METHODS AND RESULTS: We have analysed five immunodeficient patients (one with hypogammaglobulinaemia and selective IgA deficiency, one with X-linked agammaglobulinaemia, three with common variable immunodeficiency) who have been acutely infected with the same batch of intravenous immunoglobulin contaminated with hepatitis C virus (genotype 1a). The course of hepatitis C virus infection in these patients was compared to one immunocompetent patient who presented with acute hepatitis C virus and progressed to chronic disease, and seven immunocompetent patients with chronic hepatitis C. Serum samples were analysed by differential flotation ultracentrifugation in NaCl solution (density 1.063 g/ml). The high and low density fractions were tested for the presence of RNA by RT-PCR. Serum samples were also quantified for hepatitis C virus RNA (Amplicor HCV Monitor kit, Roche Diagnostic Systems). Three quarters of the acutely infected patients analysed presented with low density hepatitis C virus. Low density hepatitis C virus was absent in most chronic infections but persisted in two patients with common variable immunodeficiency. High density hepatitis C virus was detected in the chronic phase in all acutely infected patients in whom the disease persisted, and was present in all samples from PCR-positive patients with chronic infection. Immunodeficient patients had significantly higher hepatitis C virus RNA titres on presentation than immunocompetent patients, but there was no correlation between titre and clinical course of infection. CONCLUSIONS: Heterogeneities in the buoyant density of hepatitis C virus RNA have been identified in the patient groups studied. Low density hepatitis C virus is detected more often in acute infection and high density hepatitis C virus is detected more often in chronic infection. Despite acute infection via the same route of infection with the same hepatitis C virus strain, the five immunodeficient patients studied all followed a different clinical course.
Acute Disease↗
Hepatitis C virus infection in the elderly.
We studied hepatitis C virus (HCV)-related disease in older people because the treatment rationale for younger asymptomatic patients is based on the long-term prognosis of infection. Of the HCV-antibody-positive patients seen at Freeman Hospital 1990-1994, 25 were > 65 years old; 24 were Caucasian and one was Afro-Caribbean. Median age at presentation was 67 years, and five were female. Nine were asymptomatic at presentation, six presented with varices, five with malaise, three with abdominal pain, one with pruritus and one with oedema. Risk factors identified were: transfusion (7), haemodialysis (1), health care worker (dentist) (1), and tattoos (2). There was no recognized risk factor for infection in 14, but five of these had done military service in areas of high HCV prevalence. Liver biopsy in 20 showed chronic hepatitis in two, cirrhosis in 12, and cirrhosis and hepatocellular carcinoma in six. Three additional patients also developed hepatocellular carcinoma. HCV genotyping was done in 19 and all were type 1 (1a, 4; 1b, 14; 1 untypable, 1). Eleven died, at median age 71 years (range 65-94 years), five of HCV liver-related deaths and two from HCV-associated non-hepatic disorders (non-Hodgkin's lymphoma and fibrosing alveolitis).
Aged↗