Depressive symptoms in chronic hepatitis C are associated with plasma apolipoprotein E deficiency.

Neuro-psychiatric and cognitive disorders are frequent in patients with chronic hepatitis C (CHC) virus (HCV) infection which adversely impact quality of life, antiviral treatment adherence and outcome. HCV has neurotrophic properties and affects lipid metabolism, essential for cognitive function. We evaluated the relationship of lipid profiles with depression and anxiety symptoms and the effects of 12-weeks of therapy with fluvastatin and omega-3 ethyl esters (n-3 PUFA) in a randomised pilot study of CHC prior non-responders. Participants (n = 60) had fasting lipid profiles and assessment of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) questionnaire at each study visit. At screening 26/60 (43 %) had HADS-A score ≥8 and 13/60 (22 %) had HADS-D scores ≥8. Depressed patients had significantly lower apolipoprotein-E concentrations (30 mg/l vs 39 mg/l, P = 0.029) than those without depression and a tendency toward lower total cholesterol (3.8 vs 4.4 mmol/l, P = 0.053). 3 patients discontinued lipid-modifying treatment because of worsening depression. However, there was a small but significant improvement in anxiety symptoms after 12-weeks of high-dose (2-4 g daily) n-3 PUFA. In conclusion, depression in CHC is associated with plasma apoE deficiency. We postulate that apoE deficiency disrupts blood brain barrier integrity to promote HCV infection of the CNS. High-dose n-PUFAs may alleviate anxiety in some CHC patients but the use of lipid lowering therapy must be balanced against risks of worsening depression.

CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection.

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.

Targeted case finding for hepatitis B using dry blood spot testing in the British-Chinese and South Asian populations of the North-East of England.

Chronic infection with the hepatitis B virus (HBV) is a frequent cause of cirrhosis and liver cancer. Targeted HBV screening is recommended by the Centre for Disease Control (CDC) and Prevention for subjects born in countries with >2% HBV prevalence. However, there are no UK guidelines. Here, we applied the (CDC) recommendations to the British-Chinese and British-South Asian community of North-East (NE) England. British-Chinese and South Asian subjects were invited to attend for HBV education and screening sessions held in community centres. Hepatitis B surface antigen (HBsAg) and hepatitis B core total antibody (HBcAb) were tested with dry blood spot tests. South Asians were also tested for hepatitis C antibody (HCVAb). A total of 1126 subjects (606 Chinese and 520 South Asian) were screened. Sixty-two (5.5%) were HBsAg positive. Ten of these reported a previous diagnosis of HBV. The prevalence of HBsAg positivity was 4.6% when previously diagnosed individuals were excluded. The HBsAg prevalence was significantly higher in the Chinese subjects compared with South Asians (8.7% VS. 1.7% P < 0.001). In Chinese subjects, HBsAg positivity was highest in subjects born in Vietnam (17.4%), followed by China (11%), Hong Kong (7.8%) and the UK (6.7%). Subjects from Pakistan had the highest HBsAg and HCV Ab prevalence in the South Asians (3.1% and 1.8%, respectively). Ten percentage of HBsAg positive patients who had follow-up assessment had active disease requiring antiviral treatment. Undiagnosed HBV infection was above the 2% threshold for screening suggested by the CDC in the British-Chinese and Pakistani community of NE England, which provides evidence for a UK HBV-targeted screening programme.

Hepatitis C virus and atherosclerosis: A legacy after virologic cure?

Hepatitis C virus (HCV) is a major pathogen with approximately 3% of the world's population (over 170 million) infected. Epidemiological studies have shown HCV is associated with an increased risk of cardiovascular and cerebrovascular mortality as well as peripheral arterial disease. This is despite HCV inducing an ostensibly favourable lipid profile with accompanying low classical risk score for atherosclerosis (AS). We discuss possible factors involved in the aetiopathogenesis of atherosclerosis in chronic HCV and hypothesise that an important mechanism underlying the development of AS is the presence of circulating low-density immune complexes that induce an inflammatory response. We suggest that HCV particles may be inducing an antibody response to lipoproteins present in the lipoviral particles and sub-viral particles - a concept similar to the more general 'autoantibody' response to modified LDL. After virologic cure some AS risk factors will recede but an increase in serum cholesterol could result in progression of early atherosclerotic lesions, leaving a legacy from persistent HCV infection that has clinical and therapeutic implications.

Immunohistochemical assessment of hepatitis C virus antigen in cholestatic hepatitis after liver transplantation.

BACKGROUND: Patients with common variable immunodeficiency may exhibit rapidly progressive hepatitis when infected with hepatitis C virus (HCV), leading to cirrhosis and liver failure. Liver transplantation in these patients may result in a cholestatic form of HCV reinfection with exceptionally high virus loads. AIMS: To report an immunohistochemical investigation of the pretransplant and post-transplant liver of one such patient. METHODS/RESULTS: On immunohistochemical staining of frozen sections with anti-HCV core monoclonal antibody or fluorescein labelled human polyclonal anti-HCV IgG, no HCV antigens were demonstrated in the native cirrhotic liver removed at transplant, despite a viral load of 10(6.4) genomes/g. The transplanted liver, collected six weeks post-transplant, exhibited cholestatic recurrent hepatitis, had an HCV virus load of 10(10) genomes/g of liver, and revealed HCV antigen in the cytoplasm of most hepatocytes, with a pronounced periportal distribution. No virus antigen was demonstrable in other cell types. The core antigen was also detected in paraffin wax embedded, formaldehyde fixed tissue of this liver after high temperature antigen retrieval, but not in the native cirrhotic liver or a selection of HCV positive livers collected pretransplant from immunocompetent patients. Attempts to delineate the distribution of E1, NS3, and NS4 antigens were unsuccessful because monoclonal antibodies to these antigens produced "false positive" staining of foci of hepatocytes in the post-transplant livers of HCV seronegative patients with cholestasis. CONCLUSION: This case provided an opportunity to study the natural development of HCV during acute infection in the absence of an immune response, and may help to elucidate the pathogenesis of HCV recurrence in liver allografts.

Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene: lack of a polymorphism in CYP1A2 in Caucasians.

The cytochrome P450 CYP1A2 is important in the metabolism of both drugs and procarcinogens such as heterocyclic amines. We aimed to clarify the existence of a phenotypic polymorphism and explore the molecular basis of such a polymorphism. Ninety-two non-smoking individuals underwent caffeine phenotyping. The distribution of the 1,7-dimethylxanthine + 1,7-dimethyluracil/caffeine (17U + 17X/137X) ratio and log-transformed data were determined. Probit plots were constructed and the distribution fitted using maximum likelihood method. The CYP1A2 gene, including upstream regulatory regions, was examined for sequence polymorphisms using the single-strand conformation polymorphism technique in 19 individuals and by complete DNA sequencing in two individuals from the extremes of the distribution. We found a similar range (1.45-18.65) and median (6.7) for the 17U + 17X/137X ratio to that found in previous studies of non-smoking Caucasians and no effect of sex. The 17U + 17X/137X ratio gave a normal distribution when log-transformed. Maximum likelihood analysis showed that the log-normal and bimodal distributions had similar deviances but the log-normal distribution was favoured because it has fewer parameters. There was no evidence for significant DNA sequence differences between fast and slow metabolizers, although some differences from published sequences including a silent polymorhpism in exon 7 which were unlikely to be of functional significance were found. We therefore conclude that CYP1A2 does not show functionally significant polymorphism but that the wide interindividual variation in activity may be due to environmental factors.

The RsaI polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: effect on age of presentation and dependence on alcohol dehydrogenase genotype.

Twin studies in Caucasians suggest that susceptibility to alcoholic liver disease is, in part, genetically determined. Because most of the deleterious effects of alcohol are caused by its metabolism, attention has focused upon genes encoding ethanol metabolizing enzymes. Caucasians are polymorphic at only two of these gene loci--cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase 3 (ADH3). We examined the frequency of the RsaI polymorphism of CYP2E1 and ADH3 genotype in 264 patients with alcoholic liver disease and 121 local control individuals. There was a non-significant excess of the rare c2 CYP2E1 allele in patients with advanced liver disease compared with control individuals/patients with steatosis only (0.029 versus 0.017/0.00). However, patients with the c2 allele presented at a younger age compared with those with the wild type c1 allele only (42.3 +/- 1.6 years versus 49.0 +/- 0.6 years; P = 0.001) with at least as advanced histology (93% cirrhotic versus 74%). Male patients had a higher frequency of the ADH3*2/*2 genotype (which encodes the less active gamma2 subunit) than control individuals [odds ratio (OR) 2.04 (1.11-3.76)], however, ADH3 genotype did not differ with histological stage or with age of presentation. Patients with advanced disease possessing the c2 allele had a significantly higher frequency of the ADH3*2/*2 genotype compared with c1 homozygotes [OR 3.71 (1.24-11.09)]. This study demonstrates that, although rare in Caucasians, possession of the mutant c2 allele of CYP2E1 increases the risk of alcoholic liver disease at a given level of cumulative alcohol consumption. This risk appears to be particularly manifest in individuals carrying the ADH3*2 allele, presumably reflecting increased metabolism of ethanol by CYP2E1. In the absence of the c2 allele, ADH3 genotype does not influence the risk of advanced alcoholic liver disease but, in males at least, may influence the risk of alcoholism.

Characterisation of the reactivity of autoantibodies in primary biliary cirrhosis.

Autoantibodies in the sera of patients with primary biliary cirrhosis, shown previously to recognise the E2 polypeptide of the mammalian pyruvate dehydrogenase complex (PDC), have been demonstrated to react with the E2 component of PDC from bacteria (E. coli) and yeast (S. cerevisiae). Limited tryptic digestion, which cleaves E2 into well-characterised domains, followed by Western blotting indicates that the main immunodominant region of PDC E2 lies within the lipoic acid-containing domains of the polypeptide.

Polymorphisms in GSTP1, GSTM1, and GSTT1 and susceptibility to colorectal cancer.

Polymorphisms in glutathione S-transferase (GSTs) may predispose to colorectal cancer through deficient detoxification of environmental carcinogens, although previous results are conflicting. A study with 178 matched case-control pairs was conducted to determine the effect of the GSTT1 and GSTM1 null genotypes and polymorphisms in GSTP1 on colorectal cancer susceptibility. In a secondary analysis, we examined interactions between genotypes and with the N-acetyltransferase 2 (NAT2) genotype. Heterogeneity by age, sex, site, and stage of cancer was also examined. No effect of any genotype for GSTM1, GSTT1, or GSTP1 on colorectal cancer susceptibility was detected. Secondary end points showed that individuals with both the GSTT1 null and NAT2 slow genotypes combined appeared to be at increased risk of colorectal cancer (odds ratio = 2.33; 95% confidence interval, 1.1-5.0). We conclude that GST polymorphisms alone do not predispose to colorectal cancer in northeast England. We also observed possible effects of the GSTT1 null genotype on the age and stage at presentation, and these, together with the findings of an apparent interaction with NAT2 genotypes, need to be confirmed in further studies.

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.

Enhanced ultrasensitive detection of structurally diverse antigens using a single immuno-PCR assay protocol.

Our studies of DNA damage and repair in autoimmune disease, lymphomagenesis, and carcinogenesis, require identification of an immunoassay approach that is capable of ultrasensitive detection in a routine human tissue biopsy of several physicochemically diverse antigens, some of which will be present at very low level. Immuno-polymerase chain reaction (immuno-PCR) is a recently described method for ultrasensitive antigen detection that combines the amplification power of PCR with a method similar to a standard antibody capture, enzyme-linked immunosorbent assay (ELISA). As a test of the universality of immuno-PCR, and as an assessment of the suitability of this method for our studies, we used a single immuno-PCR protocol to assay purified forms of the following physicochemically diverse antigens: oligomeric pyruvate dehydrogenase complex (PDC; Mr 8.5 x 10(6)), the promutagenic DNA base adduct O(6)-methylguanosine (Mr 298) and its monomeric repair enzyme, O(6)-methylguanine-DNA methyltransferase (MGMT; Mr 22,000), and a peptide from the N-terminus of MGMT (Mr 2310). We found that all antigens could be ultrasensitively assayed using the single immuno-PCR protocol. Assay limits observed using antigen-specific (primary) antibodies at 1 microg/ml, were in the approximate range of 10(2)-10(9) molecules, with O(6)-methylguanosine being detected most sensitively. Sensitivity of the antigen assay appeared to positively correlate with primary antibody titres determined by ELISA. Furthermore, we observed a substantial increase in detection sensitivity for all antigens by the use of primary antibodies at the higher level of 10 microg/ml. The latter approach permitted antigen assay within the approximate range of 10(0)-10(7) molecules. The combination of higher titre primary antibodies and their use at higher input level, produced an increase of immuno-PCR assay sensitivity of up to four orders of magnitude greater than those previously reported through the use of this assay to measure other antigens. This represents up to a nine order of magnitude increase in immunoassay sensitivity compared to ELISA. Our findings provide compelling evidence that immuno-PCR is indeed a universal ultrasensitive antigen detection method. Using the indicated assay enhancements. immuno-PCR performed as detailed here can offer greatly increased sensitivity for antigen measurement compared to other methods. Thus, our findings suggest that parallel quantitation of several different antigens in very small samples of human tissue will be readily attainable using immuno-PCR.

Primary biliary cirrhosis: clinical and associated autoimmune features and natural history.

Primary biliary cirrhosis, a chronic liver disease, predominately affects middle-aged women. The diagnosis is established by the presence of disease-specific autoantibodies and compatible liver histology showing focal immune-mediated damage to the intrahepatic bile ducts. Patients now are detected prior to the onset of symptoms typical of cholestasis with abnormal liver function tests, or even prior to the onset of abnormal liver function tests, with positive antimitochondrial antibodies. Earlier diagnosis is changing not only our appreciation of the prevalence of this condition, but also of the natural history. The disease appears to be heterogeneous with some patients having a slow progression and a normal life-expectancy, although other patients have a more aggressive course developing symptoms and end-stage disease that leads to death or liver transplantation.

Coronary artery spasm and myocardial infarction in the absence of angiographically demonstrable obstructive coronary disease.

Myocardial infarction due to spasm of an "angiographically normal coronary artery" is rare, and its significance as a cause of myocardial infarction in patients without obstructive coronary disease has not been determined. Two patients are described with transmural myocardial infarction, nonobstructive coronary arteries, and suggestive evidence of coronary vasospasm as the cause of infarction. In one patient, angiography was carried out within 7 days of infarction and the documentation of normal coronary arteries argued strongly against a thromboembolic cause for infarction. This patient also had the combination of asthma, hypereosinophilia, and a systemic disease suggesting an immunologic disturbance with increased autoantibody production. A temporal association was noted between the episodes of asthma and those of coronary spasm during exacerbation of the eosinophilia, which raised the speculative issue of "allergic" coronary vasospasm. It is concluded that spasm of a nonobstructed coronary artery may cause transmural myocardial infarction. Further documentation is required in order to place this association in perspective among the other potential cause of infarction in patients with normal coronary artery anatomy.

Progression of autoimmune damage in primary biliary cirrhosis: an immunohistochemical study.

Aberrant MHC Class II antigen expression and the nature of the infiltrating lymphoid cells were studied by immunohistochemical techniques in liver biopsies from 37 patients with Primary biliary cirrhosis (PBC) (11 histological stage I, 13 stage II-III, 13 stage IV) and 15 patients with chronic non autoimmune liver disease. Bile duct epithelial cells expressed HLA-DR, DP and DQ antigens in biopsies from patients with early (Stage I) PBC and less frequently in the late cirrhotic phases of the disease (Stage IV); these observations support the hypothesis that induction of Class II antigens on epithelial cells may be involved in initiating autoimmune responses towards bile duct components. The presence of cytotoxic/suppressor T cells around the bile ducts in Stage I suggests a role for cell mediated destruction of the ducts at this early stage. The nature of the chronic inflammatory cell infiltrate in the portal tracts, periportal areas and lobular parenchyma does not establish the mechanism(s) involved in disease progression. However, the lack of Class II antigen expression on hepatocytes is compatible with the hypothesis that hepatocellular damage is non-specific and may be secondary to the initial bile duct injury.

Sex hormone binding globulin and non-protein-bound oestradiol in postmenopausal patients with primary biliary cirrhosis and normal controls.

Several studies have suggested that patients with primary biliary cirrhosis (PBC) have an increased risk of a number of medical conditions related to their oestrogen levels. This study has measured sex hormone binding globulin (SHBG) binding capacity, total oestradiol levels and percentage non-protein-bound (NPB) oestradiol and calculated the concentration of NPB oestradiol, in postmenopausal subjects in the following groups; normal controls, early PBC, advanced PBC and advanced PBC who were receiving therapy. Mean SHBG levels were higher in all groups of patients with PBC than in controls. No significant difference was observed in total or biologically active oestradiol between the four groups.

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.

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).

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.

Managing chronic hepatitis C acquired through intravenous drug use.

We retrospectively reviewed the provision and uptake of hospital services for 253 current and ex-intravenous drug users with hepatitis C virus (HCV). Overall, 237 attended at least one clinic (mean age 32 years, 70% male, 43% on maintenance methadone); 81% had evidence of active viral replication and 137 agreed to a liver biopsy to assess disease severity. Of these 137, 24% had mild chronic hepatitis with a low risk of progression to cirrhosis, but 9% had cirrhosis (mean age 40 years, mean time since initial intravenous drug use 15.8 years). Only 50 of the 100 patients in whom antiviral therapy was indicated, commenced treatment; 18 (36%) have had a sustained virological response. The natural history or response to treatment of chronic HCV in those who acquire it through intravenous drug use is not different to that previously reported for post-transfusion HCV. However, a substantial proportion default from follow-up or decline further intervention. As intravenous drug use is now the main risk factor for acquisition of HCV, these data have implications for future delivery of care aimed at limiting the morbidity of chronic HCV, and limiting the spread of hepatitis C virus infection amongst intravenous drug users.

Non-Hodgkin's lymphoma and hepatitis C virus infection.

The hepatitis C virus (HCV) is a recently described and important cause of acute and chronic liver disease. A hallmark of HCV is its propensity to become chronic, some patients with chronic HCV progressing to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotrophic and we report 2 patients with HCV cirrhosis who developed non-Hodgkins lymphoma (NHL). These cases raise the possibility that chronic HCV infection of lymphocytes plays an aetiological role in this malignancy. However screening of a further 63 consecutive patients over the age of 50 years with NHL for HCV antibody by second generation enzyme linked immunoassay (ELISA) failed to identify any patients with evidence of HCV infection. This suggests that HCV is an uncommon contributory factor for the development of non-Hodgkins lymphoma in the United Kingdom.