The necessity of education and hepatitis B vaccination for young people: A study of high risk behaviour for blood borne viruses in the United Kingdom.

Blood borne virus (BBV) infection in adults involved in high risk behaviour is well recognized. There are limited reported data on young people involved in high risk behaviour. A descriptive questionnaire was used to ascertain risk behaviour at the Young People's Substance Misuse Service (Birmingham). Data collection included risk behaviour and serological tests for hepatitis B, C and HIV. Sixty-five of one-hundred three (63%) young people participated; 37/65 male; age range 13.9-18.9 (median 17.4 years). Risk behaviour included 6 intravenous drug, 58 cannabis, and 61 had sexual partners, of whom 52 (85%) engaged in unprotected sex. Sixty-five participants were negative for BBV infection: 9 were HBV immune. HB vaccination was not available at the centre (for <18 year), and all refused referral to their general practitioner for vaccination due to fear of disclosure. The main risk for BBV acquisition was unprotected sex with multiple sexual partners and illicit drug use. Most were unaware of the risks related to high risk behaviour. Effective education programmes of relevant risk factors with HBV vaccination should be implemented during preadolescence. We recommend an integrated service via specialized centres, to work together to improve awareness and increase efforts to vaccinate adolescents at risk for HBV infection.

A 10-year longitudinal follow-up study of a U.K. paediatric transplant population to assess for skin cancer.

BACKGROUND: Our earlier study, published in 2004,found no skin cancer in a cohort of paediatric organ transplant recipients (POTRs) 5-16 years post-transplantation. We re-evaluated the same cohort 10 years later. OBJECTIVES: To determine the prevalence of premalignant and malignant skin lesions and identify known risk factors associated with melanocytic naevi in a U.K. paediatric transplant population. METHODS: Ninety-eight POTRs from the original 2004 study were invited to participate in this longitudinal follow-up study. History of sun exposure, demographics and transplantation details were collected using face-to-face interviews, questionnaires and case note reviews. Skin examination was performed for regional count of malignant lesions, benign and atypical naevi. RESULTS: Of the 98 patients involved in the initial study, 45 POTRs (eight kidney, 37 liver), with a median follow-up of 19 years (range 15-26 years), agreed to participate. Neither skin cancer nor premalignant lesions were detected in these patients. When compared with the 2004 cohort, 41 patients in our current cohort had increased numbers of benign naevi (P < 0·001) with 11 patients having ≥ 50 benign naevi. Seventy-one per cent of benign naevi in our 2014 cohort occurred on sun-exposed sites (13% head/neck, 35% arms and 23% legs). Patients who regularly used sunscreen had more benign naevi on their arms (P = 0·008). CONCLUSIONS: Although skin cancer was not observed in our cohort, we identified a significant increase in the number of benign naevi, particularly in those reporting frequent sunburn and sunscreen use.

Parents in transition: Experiences of parents of young people with a liver transplant transferring to adult services.

Predictors of successful transition from pediatric to adult services include ability to self-manage and engage with healthcare services. Parents have a key role in healthcare management throughout childhood and adolescence including encouraging development of self-management skills in their children. Transition to adult services can be challenging for parents and young people, yet parents' views regarding transition remain largely unexplored. Nine parents of pediatric liver transplant recipients (15.2-25.1 yr) participated in semistructured interviews. Interviews were analyzed using IPA. Analysis revealed three key themes: "emotional impact of transplantation," "protection vs. independence," and "ending relationships and changing roles." Parents expressed the dichotomous nature of the desire to promote independence in their child while still maintaining control and protection, and discussed how changing roles and relationships were difficult to navigate. Parents are important facilitators of young people's development of self-management skills for successful transfer to adult services. Parents should be supported to move from a "managerial" to a "supervisory" role during transition to help young people engage independently with the healthcare team. Findings support the development of interventions for parents to emphasize their role in transition and guide the transfer of self-management skills from parent to young person.

"Are these adult doctors gonna know me?" Experiences of transition for young people with a liver transplant.

Excellent survival rates in paediatric LTx have resulted in increasing numbers of young people transferring from paediatric to adult care. Understanding the mechanisms of successful transition is imperative for ensuring good long-term outcomes and developing services for young people. Semi-structured interviews were conducted with 17 young people (10 females; age range: 15.2-25.1 years). Eight were within 1 year of transferring to adult services; nine had transferred. Interviews were analysed using IPA. Analysis revealed two major themes in both pre- and post-transfer groups: "relationships with healthcare professionals" and "continuity of care." Young people experienced difficulty ending relationships with paediatric clinicians and forming new relationships with adult clinicians. They expressed frustrations over a perceived lack of continuity of care after transfer and a fear of the unknown nature of adult services. The importance of a holistic approach to care was emphasized. Interventions are needed to support young people in transition, particularly in ending relationships in paediatric care and forming new relationships in adult care. Young people need help to develop strategies to cope with the different approaches in adult services. Interventions to provide clinicians with skills to communicate and engage with young people are imperative.

Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N.

Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of parkinsonism.

Selenium homocholic acid taurocholate scanning, selenium-75-labeled bile acid, a novel method for testing the function of the terminal ileum in small bowel transplant recipients: a pilot study.

INTRODUCTION: The terminal ileum (TI) is important for the active reabsorption of bile salts and is the site of allograft rejection; disruption of enterohepatic circulation (EHC) may give insights to inflammatory and other physiologic processes at the TI. SUBJECTS AND METHODS: Four children aged 5 to 12 years who had received small bowel transplantation (SBTx), 3 recovering from post-transplant lymphoproliferative disease (PTLD) and 1 with acute rejection, were studied. Two of the 4 had stoma reversal. Another child (15 years) with progressive familial intrahepatic cholestasis (PFIC) and pruritus, despite liver transplantation and biliary diversion, was studied. Selenium homocholic acid taurocholate scanning ((75)SeHCAT) capsule was given orally (n = 3) or via introducer during endoscopy (n = 2); a baseline whole-body gamma camera scan was done 4 hours later and on days 1 to 5. RESULTS: The normal 3-day bile salt retention is 30% to 70% of baseline and normal adult biological half-life, t½ is 62 ± 17 hours. The results in children with a stoma were very low (0.1% at 7.6 hours; 5% at 17 hours). The children with reversed stoma had retention and t½ closer to the reference range (18% at 29 hours; 22% at 33 hours). The child with PFIC + biliary diversion had an initial very high gamma emission from the stoma bag suggesting excellent reabsorption of bile salts from his TI, but retention was 0.6% and t½ 9.8 hours, demonstrating efficient biliary diversion. CONCLUSION: These results confirm children with stomas malabsorb bile acids, which can be ameliorated after stoma closure. SeHCAT demonstrated that the biliary diversion was working well and may be helpful in preoperative assessment of abnormal EHC. The role of SeHCAT in SBTx requires further evaluation.

Treatment of chronic viral hepatitis C in children and adolescents: UK experience.

AIM: To review the efficacy and tolerability of pegylated interferon-α and ribavirin for treatment of chronic hepatitis C (CHC) in children in the UK. METHODS: Retrospective review of children treated for CHC in 3 UK paediatric specialist liver centres between 2005 and 2010. Data on viral response to treatment, demographic and clinical details were collected. Treatment outcome was assessed by the absence of detectable viral RNA in blood 24 weeks after treatment-sustained viral response (SVR). RESULTS: 75 children were included; 34 genotype 1; 39 genotypes 2 and 3; 2 genotype 4. Overall SVR was achieved in 54/71 (76%); 65% genotype 1; 89% genotypes 2 and 3; 100% genotype 4. Early response at 12 weeks was achieved in 53 and sustained in 47 (89%). Data on rapid response after 4 weeks of treatment were available in 25; 17/25 (68%) responded and 16 of these (94%) achieved SVR. IL28 T/T genotype was associated with higher SVR. There were no significant changes in weight and height z scores from baseline compared with 24 weeks post-treatment follow-up. No child discontinued treatment due to side effects, although 43 required dose modification. Treatment affected quality of life (QoL) in the initial 12 weeks of treatment, which improved by the end of treatment. CONCLUSIONS: Children respond well to therapy for CHC. Treatment was tolerated with minimal impact on QoL and no significant effect on growth. Knowledge of viral and IL28 genotypes and early viral response is useful to plan treatment in children and provide appropriate counselling.

Differential control of sex differences in estrogen receptor α in the bed nucleus of the stria terminalis and anteroventral periventricular nucleus.

The principal nucleus of the bed nucleus of the stria terminalis (BNSTp) and anteroventral periventricular nucleus of the hypothalamus (AVPV) are sexually dimorphic, hormone-sensitive forebrain regions. Here we report a profound sex difference in estrogen receptor-α (ERα) immunoreactivity (IR) in the BNSTp, with robust ERα IR in females and the near absence of labeling in males. This sex difference is due to the suppression of ERα IR by testicular hormones in adulthood: it was not present at birth and was not altered by neonatal treatment of females with estradiol; gonadectomy of adult males increased ERα IR to that of females, whereas gonadectomy of adult females had no effect. Treating gonadally intact males with an aromatase inhibitor partially feminized ERα IR in the BNSTp, suggesting that testicular suppression required aromatization. By contrast, in AVPV we found a modest sex difference in ERα IR that was relatively insensitive to steroid manipulations in adulthood. ERα IR in AVPV was, however, masculinized in females treated with estradiol at birth, suggesting that the sex difference is due to organizational effects of estrogens. The difference in ERα IR in the BNSTp of males and females appears to be at least in part due to greater expression of mRNA of the ERα gene (Esr1) in females. The sex difference in message is smaller than the difference in immunoreactivity, however, suggesting that posttranscriptional mechanisms also contribute to the pronounced suppression of ERα IR and presumably to functions mediated by ERα in the male BNSTp.

Penile anatomy and hypotheses of erectile function in the American alligator (Alligator mississippiensis): muscular eversion and elastic retraction.

The intromittent organs of most amniotes contain variable-volume hydrostatic skeletons that are stored in a flexible state and inflate with fluid before or during copulation. However, the penis in male crocodilians is notable because its shaft does not seem to change either its shape or bending stiffness as blood enters its vascular spaces before copulation. Here I report that crocodilians may have evolved a mechanism for penile shaft erection that does not require inflation and detumescence. Dissections of the cloaca in sexually mature male American alligators (Alligator mississippiensis) show that the cross section of the proximal shaft of the alligator penis contains dense collagenous tissues that do not significantly change shape when fluid is added to the central vascular space. The large amount of collagen in the wall and central space of the alligator penis stiffen the structure so it can be simply everted for copulation and rapidly retracted at its completion. Because no muscles insert directly onto the penis, eversion and retraction must be produced indirectly. My results suggest that the contraction of paired levator cloacae muscles around the anterior end of the cloaca rotates the penis out of the cloacal opening and strains the ligamentum rami that connect the base of the penis to the ischia. When the cloacal muscles relax, the elastic recoil of the ligamentum rami can return the penis to its original position inside the cloaca.

Hepatitis B virus transmission in pre-adolescent schoolchildren in four multi-ethnic areas of England.

The aim of this study was to estimate the amount of childhood hepatitis B virus transmission in children born in the UK, a very low-prevalence country, that is preventable only by universal hepatitis B immunization of infants. Oral fluid specimens were collected from schoolchildren aged 7-11 years in four inner city multi-ethnic areas and tested for the presence of antibody to hepatitis B core antigen (anti-HBc). Those found positive or indeterminate were followed up with testing on serum to confirm their hepatitis B status. The overall prevalence of anti-HBc in children was low [0.26%, 95% confidence interval (CI) 0.14-0.44]. The estimated average annual incidence of hepatitis B was estimated to be 29.26/100 000 children (95% CI 16.00-49.08). The total incidence that is preventable only by a universal infant immunization programme in the UK was estimated to be between 5.00 and 12.49/100 000. The study demonstrates that the extent of horizontal childhood hepatitis B virus transmission is low in children born in the UK and suggests that schools in the UK are an uncommon setting for the transmission of the virus. Targeted hepatitis B testing and immunization of migrants from intermediate- and high-prevalence countries is likely to be a more effective measure to reduce childhood transmission than a universal infant immunization programme.

Durability of sustained response shown in paediatric patients with chronic hepatitis C who were treated with interferon alfa-2b plus ribavirin.

Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Chronic hepatitis C in children--review of natural history at a National Centre.

The natural history of hepatitis C virus (HCV) infection in adults has been established, but less is known about outcome in children. We conducted a retrospective review of patients referred to Birmingham Children's Hospital Liver Unit, from 1991 till 2008, with the diagnosis of HCV was undertaken. Only children with documented positive HCV RNA and a minimum duration of follow-up of 6 months were included. One hundred and thirty-three children were identified. The route of transmission was transfusion acquired in 47%, vertically acquired in 49% and transplantation in 2%. Since 2000, most children were infected vertically. The overall rate of spontaneous viral clearance was 17.5% with higher clearance (27%) in the transfusion group compared to the vertically acquired group (9%). Seventy-six had a liver biopsy at diagnosis. There was no evidence of fibrosis in 46%, mild fibrosis in 50% and moderate to severe fibrosis in 4%. None had cirrhosis. There was a statistically significant relationship between fibrosis score and older age at the time of biopsy (P = 0.02) and longer duration of infection (P = 0.05). Eighty children received treatment for HCV. Sustained viral response (SVR) was influenced by viral genotypes, with significantly increased response rates in genotypes (G) 2 and 3 compared to G 1 and 4. Vertical infection is now the major route of HCV infection in children in the UK. Histological changes were mild at diagnosis, but the severity of fibrosis progressed with age. Consideration should be given to improve detection and diagnosis to refer children to specialist centres for management and antiviral therapy before developing fibrosis.

The challenges and opportunities for transitional care research.

The provision of healthcare for young people with solid organ transplants as they move into adult-centered services has received increasing attention over recent years particularly as non-adherence and graft loss increase after transfer. Despite medical advances and that transitional care is now well established on national and international health agendas, progress in the research arena has unfortunately been slow. The aims of this paper are to consider why this is and discuss the particular challenges facing clinical researchers working within the area.

Liver transplantation in children using non-heart-beating donors (NHBD).

Selected livers from controlled NHBD are accepted for OLT in adults. Recent evidence has shown good medium-term outcome. The purpose of this study was to report our experience of pediatric OLT with whole and partial grafts from NHBD, analyzing complications and outcome. Retrospective review of all the recipients who underwent primary OLT between December 2005 and December 2008, using livers from NHBD. Four children (one male child) mean age was 9.5 yr (0.2-17), mean weight was 26 kg (range 2.6-48), underwent OLT using NHBD. Mean donor age was 14.2 yr, and mean WIT (systolic BP<50 mmHg to cold perfusion) 12.2 min (range 10-15). Two children received reduced grafts and two full grafts. Mean cold ischemia time was 7.18 h (range 6-8). Liver function tests one wk and nine months post-OLT confirmed a good graft function. One child was treated for two episodes of acute rejection. Post-transplant complications included two cases of mild ischemic cholangiopathy treated conservatively. Graft and patient survival was 100% with a mean follow-up of 19 months (range 8.1-43.4). Short- to medium-term follow-up suggests that liver grafts from young NHBD with short warm and cold ischemia times can be safely utilized in pediatric transplantation.

Isolated liver transplant in infants with short bowel syndrome: insights into outcomes and prognostic factors.

OBJECTIVE: Selected infants with short bowel syndrome (SBS) and progressive intestinal failure associated liver disease (IFALD) may benefit from isolated liver transplantation (iLTx). The aim of the study is to identify risk factors for unfavourable outcome in iLTx. PATIENTS AND METHODS: A retrospective review of medical records from 1998 to 2005 was undertaken. Risk factors were assessed by comparing long-term survivors with those who died after iLTx. RESULTS: Fifteen iLTx were performed in 14 infants with IFALD. All were parenteral nutrition (PN) dependent, but had tolerated enterally 54% (38-100) of energy intake before iLTx. Median residual bowel was 60 cm (30-200). Eight out of 14 had intact ileocaecal valve (ICV). Median bilirubin was 298 micromol/L (87-715) and all had portal hypertension. Eight out of 9 survivors were weaned from PN after median 15 months. In 4 out of 9 children, nontransplant surgery after iLTx facilitated intestinal adaptation. Growth velocity had improved at 3 years after iLTx (P=0.001). Five children who died had poor enteral tolerance following iLTx (P<0.002), which correlated with pretransplant dysmotility seen in 4 out of 5 children shown by contrast studies (P=0.02)and increased frequency of line infections before (>6/year P<0.04) and after (P<0.001) iLTx. CONCLUSIONS: Isolated liver transplantation is a lifesaving option for selected children with SBS and IFALD. Revised criteria are proposed: progressive IFALD; 50 cm functional bowel in absence of ICV or 30 cm with ICV; 50% daily energy intake tolerated enterally for 4 weeks with satisfactory growth; and children with dysmotile bowel should be assessed for combined liver/bowel transplant unless the dysmotility is resolved and associated with minimal line infections.

Skin surveillance of a U.K. paediatric transplant population.

BACKGROUND: Solid organ transplant recipients are at increased risk of skin cancer. Melanoma is less common than nonmelanoma skin cancer (NMSC) although the relative proportion of melanoma among skin cancers has been shown to be higher in paediatric than adult recipients. Multiple melanocytic naevi and/or atypical naevi may be a risk factor for the development of melanoma. The relationship between naevus counts and phenotypic characteristics, disease-related variables and sun exposure has not been explored in paediatric transplant patients. OBJECTIVES: To determine the prevalence of premalignant and malignant skin lesions and to identify known risk factors associated with benign and atypical melanocytic naevi in a U.K. paediatric transplant population. METHODS: Paediatric (< or = 19 years) renal and liver transplant patients, who were 5 or more years post-transplantation, were reviewed over 12 months. Lifetime history of sun exposure, episodes of sunburn, sunny holidays, sunscreen use, sun bed use, demographic and transplantation details were collected using interview, questionnaire and case note review. A skin examination was performed for regional counts of malignant lesions, benign and atypical naevi. RESULTS: Ninety-eight patients (82 liver, 13 renal, three multiorgan) with a median follow up of 9 years (range 5-16) were reviewed. Neither skin cancer nor premalignant lesions for NMSC were detected in this group. Eighty-five patients had benign naevi (median 6, range 1-57). Clinical risk factors for increased counts of benign naevi included increasing age (P = 0.03), more episodes of sunburn (P = 0.003) and prolonged treatment with cyclosporin (P = 0.009). The presence of atypical naevi in six patients was significantly associated with more episodes of sunburn (P = 0.006) and more transplants (P = 0.04). Other variables including phenotype, skin type, sun exposure, holidays abroad, residence abroad and total duration of immunosuppression did not correlate with benign or atypical naevus counts. CONCLUSIONS: Skin cancer was not observed in paediatric solid organ transplant recipients who were 5-16 years post-transplantation. Both benign and atypical naevus counts were higher in children with frequent episodes of sunburn. As both naevi and sunburn are risk factors for melanoma, we should target fair-skinned transplant recipients with naevi for intensive sun avoidance education. A prospective, longitudinal follow-up study should determine the onset of skin cancer post-transplantation and the significance of benign and atypical naevus counts in this cohort.

Current issues in pediatric transplantation.

Pediatric solid organ transplantation is so successful that >80% of children will survive to become teenagers and adults. Therefore, it is essential that these children maintain a good quality life, free of significant long-term side effects. While intensive immunosuppressive regimens (containing CsA, tacrolimus, MMF, and steroids) effectively reduce acute or chronic rejection, they can produce long-term side effects including viral infection, renal dysfunction, hypertension, and stunting. The development of effective methods of diagnosis, prevention, and treatment of CMV means that this is no longer a significant cause of mortality, but morbidity remains high. In contrast, infection rates of EBV remain high in EBV-negative pre-transplant patients. However, pre-emptive reduction of immunosuppression or treatment with rituximab or adoptive T-cell therapy is effective in preventing/treating post-transplant lymphoproliferative disease. Recent protocols have concentrated on reducing CsA immunosuppression, to prevent unacceptable cosmetic effects, and to reduce the hypertension, hyperlipidemia, and nephrotoxicity. Both CsA and tacrolimus cause a 30% reduction in renal function, with 4-5% of patients developing severe chronic renal failure. The use of IL-2 inhibitors for induction therapy with low-dose calcineurin inhibitors, in combination with renal-sparing drugs such as MMF or sirolimus for maintenance immunosuppression, should prevent significant renal dysfunction in the future. The concept of steroid-free immunosuppression with IL-2 inhibitors, tacrolimus, and MMF is an attractive option, which may reduce stunting and renal dysfunction. However, these regimens may be associated with the increased development of de-novo autoimmune hepatitis in 2-3% of children. The most important challenge to long-term survival in transplanted children is the management of non-adherence and other adolescent issues, particularly when transferring to adult units, as this is the time when many successful transplant survivors lose their grafts.

Is serum gentamicin level a good predictor of graft injury in intestinal transplantation?

INTRODUCTION: Following intestinal transplant (SBT), the early diagnosis and treatment of rejection is a major management aim. The diagnosis of rejection is based on histology of stomal biopsies. Oral gentamycin (2.5 mg/kg) was used for selective decontamination of the digestive system. Our hypothesis was that gentamycin might be absorbed in the presence of graft dysfunction. AIM: Our goal was to assess the correlation between serum gentamycin level and the health of the intestinal graft. SUBJECTS AND METHODS: Among 33 SBT performed from 1993 to 2005, serum gentamycin levels were performed once weekly or more often when there was a suspicion of rejection. All data were analyzed retrospectively. RESULTS: Adequate trough levels were achieved for only 23 patients, six of whom had histologically proven rejection and only one did not have a raised gentamycin content. Five patients with raised levels but no rejection included two with severe intestinal ischemia and three with bowel obstruction/ileus. Four of the five patients required laparotomies. CONCLUSION: We concluded that in our study raised serum gentamycin levels were a good predictor of rejection or significant injury to the graft.

Perinatal hepatitis C virus infection: diagnosis and management.

Hepatitis C virus (HCV) infection in children is becoming an increasing challenge to health professionals. As our understanding of the disease evolves, so must our diagnostic and management strategies. In the 1990s, when HCV testing became available, children identified with HCV infection in the UK were mostly those who had required blood products, particularly those with haematological disorders. Acquiring knowledge of the natural history of HCV infection was confounded by the co-morbidity of iron overload, viral co-infection, and chemotherapy.