A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Public attitudes towards novel reproductive technologies: a citizens' jury on mitochondrial donation.

STUDY QUESTION: Does an informed group of citizens endorse the clinical use of mitochondrial donation in a country where this is not currently permitted? SUMMARY ANSWER: After hearing balanced expert evidence and having opportunity for deliberation, a majority (11/14) of participants in a citizens' jury believed that children should be able to be born using mitochondrial donation. WHAT IS KNOWN ALREADY: Research suggests that patients, oocyte donors and health professionals support mitochondrial donation to prevent transmission of mitochondrial disease. Less is known about public acceptability of this novel reproductive technology, especially from evidence using deliberative methods. STUDY DESIGN, SIZE, DURATION: This study comprised a citizens' jury, an established method for determining the views of a well-informed group of community members. The jury had 14 participants, and ran over one and a half days in 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Jurors were members of the public with no experience of mitochondrial disease. They heard and engaged with relevant evidence and were asked to answer the question: 'Should Australia allow children to be born following mitochondrial donation?' MAIN RESULTS AND THE ROLE OF CHANCE: Eleven jurors decided that Australia should allow children to be born following mitochondrial donation; 7 of whom added conditions such as the need to limit who can access the intervention. Three jurors decided that children should not (or not yet) be born using this intervention. All jurors were particularly interested in the reliability of evidence, licensing/regulatory mechanisms and the rights of children to access information about their oocyte donors. LIMITATIONS, REASONS FOR CAUTION: Jurors' views were well informed and reflected critical deliberation and discussion, but are not intended to be representative of the whole population. WIDER IMPLICATIONS OF THE FINDINGS: When presented with high quality evidence, combined with opportunities to undertake structured deliberation of novel reproductive technologies, members of the public are able to engage in detailed discussions. This is the first study to use an established deliberative method to gauge public views towards mitochondrial donation. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a University of Sydney Industry and Community Collaboration Seed Award (2017), which was awarded contingent on additional funding from the Mito Foundation. Additional funding was provided by the Mito Foundation. The Foundation was not involved in jury facilitation or deliberation, nor analysis of research data. TRIAL REGISTRATION NUMBER: Not applicable.

The Royal Free Hospital 'hub-and-spoke network model' delivers effective care and increased access to liver transplantation.

OBJECTIVES: 'Hub-and-spoke' networks may be one solution to reduce the geographical inequality in access to liver transplantation (LT) and the growing demands on, and saturation of, LT centres. It is not clear if such networks improve equity of access, deliver comparable patient outcomes or effect patient satisfaction. STUDY DESIGN: Retrospective evaluation of outcomes and patient satisfaction within the Royal Free liver transplant 'hub-and-spoke' network. METHODS: Patient outcomes in those assessed for LT between September 2011 and 2014 at spoke centres (n = 4) were compared retrospectively with those assessed at the LT hub centre. Patient satisfaction questionnaires were completed and changes in LT referral patterns were explored with data obtained directly from NHS Blood and Transplant (NHSBT). RESULTS: A total of 655 patients (180 spoke; 475 hub) were assessed for LT. Patients referred from spoke centres were more likely to have viral hepatitis as an underlying aetiology (72/180 vs 110/475; P < 0.001), or hepatocellular carcinoma (48/180 vs 60/475; P < 0.001) as an indication for LT and were more likely to be listed for LT when compared with hub patients (139/180 vs 312/475, P = 0.005). Mortality on the waiting list (9/123 vs 25/269, P = 0.57), waiting time to LT (64-days vs 78-days, P = 0.91) and Model for End-Stage liver disease (MELD)/United Kingdom End-Stage Liver Disease (UKELD) score (P = 0.24/0.26) in listed patients were equivalent as were 1- and 3-year patient and graft survival rates. Patient satisfaction rates were high at both types of centre, with significantly more patients preferring 'locally delivered care' at spoke vs hub (11/50 vs 70/73, P≤0.0001). Since the development of formal hub-and-spoke networks data from NHSBT based on postcode confirmed a significant increase in patients undergoing LT (153%) from spoke centres, whereas numbers assessed and transplanted from the hub centre have remained static. CONCLUSION: Hub-and-spoke LT networks are effective in offering equivalent clinical outcomes, high patient satisfaction and alleviate clinical pressure on the hub centre. They have to potential to help eliminate the geographical disparity in mortality rates from chronic liver disease.

Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes.

OBJECTIVE: Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA). DESIGN: 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy. RESULTS: No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted. CONCLUSIONS: Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276--Randomised study for immunosuppression regimen in liver transplantation.

De novo use of generic tacrolimus in liver transplantation - a single center experience with one-yr follow-up.

UNLABELLED: Use of generic tacrolimus in liver transplantation (LT) could result in cost savings. Generic tacrolimus has been shown to be bioequivalent to innovator tacrolimus in healthy volunteers and renal transplant patients. There are limited data on the de novo use of generic tacrolimus in LT. This study aimed to determine whether the de novo use of generic tacrolimus (Adoport, Sandoz,UK) was associated with differences in outcomes, safety, and cost compared with innovator tacrolimus (Prograf, Astellas, Japan). METHODS: Patients were studied before and after a programmatic change from de novo IS with Prograf to Adoport. Outcomes, tacrolimus levels, doses, and costs were compared for the first-yr post-LT. RESULTS: Ninety-four patients were studied, 46 Prograf, 48 Adoport. No significant differences in rejection, cytomegalovirus infection, acute kidney injury, sepsis, or graft loss were observed between groups. Tacrolimus costs were significantly reduced with the de novo use of Adoport. Day 14 dose normalized levels in Adoport patients showed significant variation but at the day 30 and one yr, there were no significant differences in the doses or levels of tacrolimus between groups. CONCLUSIONS: Adoport is safe and effective compared to Prograf when used de novo in LT patients. Tacrolimus costs were significantly reduced by the use of Adoport.

Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

Evidence for reproductive philopatry in the bull shark Carcharhinus leucas.

Reproductive philopatry in bull sharks Carcharhinus leucas was investigated by comparing mitochondrial (NADH dehydrogenase subunit 4, 797 base pairs and control region genes 837 base pairs) and nuclear (three microsatellite loci) DNA of juveniles sampled from 13 river systems across northern Australia. High mitochondrial and low microsatellite genetic diversity among juveniles sampled from different rivers (mitochondrial φ(ST) = 0·0767, P < 0·05; microsatellite F(ST) = -0·0022, P > 0·05) supported female reproductive philopatry. Genetic structure was not further influenced by geographic distance (P > 0·05) or long-shore barriers to movement (P > 0·05). Additionally, results suggest that C. leucas in northern Australia has a long-term effective population size of 11 000-13 000 females and has undergone population bottlenecks and expansions that coincide with the timing of the last ice-ages.

Atypical odontalgia--a diagnostic dilemma.

Atypical odontalgia (AO) is a chronic orofacial pain condition of unclear pathophysiology, often presenting as toothache or pain at an extraction site. Idiopathic, psychogenic, vascular, and neuropathic causes have been proposed. In view of demonstrable somatosensory changes, and responses to management proposed for other forms of neuropathic pain, the best current evidence supports a neuropathic hypothesis. It is proposed that certain individuals with as-yet-undefined genetic vulnerability can develop AO when exposed to certain risk factors, including invasive dental treatment. The diagnosis and treatment of AO can be challenging, but can be aided by a multidisciplinary approach. Two cases of differing complexity are presented in this paper.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

Prevalence of genetic haemochromatosis and iron overload in patients attending rheumatology and joint replacement clinics.

BACKGROUND & AIMS: Genetic Haemochromatosis (GH) is common in North European and Celtic populations and is associated with arthropathy. We aimed to measure the frequency of the common GH mutations (C282Y and H63D), the carrier frequency of C282Y and markers of iron overload in patients who were referred to our rheumatology and joint replacement clinics. METHODS: Unselected patients attending these clinics were anonymously tested for the described mutations. Transferrin saturation and serum ferritin were also measured and if elevated, the patients had predictive counselling then named GH mutation testing. The carrier and mutation frequencies were also determined in 340 local controls. RESULTS: One hundred and sixty-one unselected patients attending these clinics were studied. The C282Y mutation carrier frequency was 1 in 5.2 in patients compared with 1 in 8.1 in controls (p < 0.005). The overall mutation frequencies were similar in patients and controls. One patient was found to be a homozygous for the C282Y mutation and eight were compound heterozygotes. Seven other patients had a raised ferritin, one of whom was a C282Y heterozygote. CONCLUSION: The C282Y carrier frequency is significantly higher in patients attending rheumatology and joint replacement clinics than in controls. Screening of these patients for GH should be considered.

Oromandibular dystonia following dental treatment: case reports and discussion.

Oromandibular dystonia (OMD) is a movement disorder characterised by involuntary, repetitive, and patterned muscle contractions of varying severity, affecting the jaws, tongue, face, and pharynx. It is most commonly idiopathic or medication-induced, but peripheral trauma sometimes precedes the condition. There have been several reports of OMD following dental treatment, and this paper discusses two cases which occurred following extractions and full dentures.

Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations.

AIM: To identify the genetic aetiology of a distinct leukoencephalopathy causing acute neurological regression in infancy with apparently complete clinical recovery. METHODS: We performed trio whole genome sequencing (WGS) to determine the genetic basis of the disorder. Mitochondrial function analysis in cultured patient fibroblasts was undertaken to confirm the pathogenicity of candidate variants. RESULTS: The patient presented at 18 months with acute hemiplegia and cognitive regression without obvious trigger. This was followed by clinical recovery over 4 years. MRI at disease onset revealed bilateral T2 hyperintensity involving the periventricular and deep white matter and MR spectroscopy of frontal white matter demonstrated a lactate doublet. Lactate levels and mitochondrial respiratory chain enzyme activity in muscle, liver and fibroblasts were normal. Plasma glycine was elevated. The MRI abnormalities improved. WGS identified compound heterozygous variants in BOLA3: one previously reported (c.136C>T, p.Arg46*) and one novel variant (c.176G>A, p.Cys59Tyr). Analysis of cultured patient fibroblasts demonstrated deficient pyruvate dehydrogenase (PDH) activity and reduced quantity of protein subunits of mitochondrial complexes I and II, consistent with BOLA3 dysfunction. Previously reported cases of multiple mitochondrial dysfunctions syndrome 2 (MMDS2) with hyperglycinaemia caused by BOLA3 mutations have leukodystrophy with severe, progressive neurological and multisystem disease. CONCLUSIONS: We report a novel phenotype for MMDS2 associated with apparently complete clinical recovery and partial resolution of MRI abnormalities. We have identified a novel disease-causing variant in BOLA3 validated by functional cellular studies. Our patient's clinical course broadens the phenotypic spectrum of MMDS2 and highlights the potential for some genetic leukoencephalopathies to spontaneously improve.

Impact of a genetic diagnosis of a mitochondrial disorder 5-17 years after the death of an affected child.

This study used in-depth interviews to explore the experiences of parents who were re-contacted with new genetic results many years after the death of a child with a mitochondrial disorder. At the time of their child's illness, parents had consented to a tissue sample being taken to help with diagnosis of a suspected mitochondrial disorder, and subsequently further DNA testing identified the genetic cause. Parents did not express negative feelings about being re-contacted with new information, and hoped that continuing research might help other families. Positive aspects included relief from feelings of guilt over the cause of the child's disorder, and having accurate genetic information available for surviving children. Difficult emotional and psychosocial implications included contradictions to previous beliefs about inheritance, deciding how and when to communicate information to surviving children, and coping with new fears for the mother's health if a gene located in the mitochondrial DNA was identified. In half of the families the new results significantly altered the parents' understanding of the inheritance pattern. This study highlights the impact of new genetic information offered after a delay of several years, which has the potential to re-open feelings of grief and uncertainty and can present a new inheritance scenario for which research participants or their families are unprepared. Health professionals involved in conveying genetic research results can help to support families through this process.

Diagnostic utility of hepatitis E virus antigen-specific ELISA versus PCR testing in a cohort of post liver transplant patients in a large university hospital.

BACKGROUND: Hepatitis E virus (HEV) is an important infectious agent causing acute and chronic disease. Chronic hepatitis E affects immunocompromised people and serological testing is neither reliable nor sufficient to infer whether a patient has infection; therefore HEV RNA testing is the only reliable diagnostic test presently available. An HEV antigen-specific ELISA test is commercially available but is not yet in clinical use. OBJECTIVES: 1) determine the prevalence of HEV infection in the Royal Free Hospital (RFH) liver transplant cohort; 2) compare the diagnostic utility of HEV antigen-detection against the current gold standard; 3) consider screening strategies for HEV infection in immunocompromised groups. STUDY DESIGN: The serum samples of 490 post liver transplant patients visiting the outpatient clinic at the RFH over an eight-month period were tested for HEV with both an HEV antigen-specific ELISA and HEV RNA test. RESULTS: The prevalence of HEV infection was 0.20% (95% CI 0.0%-1.1%). The specificity of the ELISA was 98.2% with a positive predictive value of 10.0%. There was one true positive HEV case, which was picked up correctly by the antigen-specific ELISA. These results were improved by incorporating a neutralisation step into further ELISA tests. CONCLUSIONS: The antigen-specific ELISA test gave no false negative results, supporting its utility as a screening tool. There was one true antigen positive result. Further investigation including cost analysis is indicated to determine the efficacy of HEV antigen-specific ELISA testing in a screening context and in the clinical investigation of HEV infection in immunocompromised patients.

Serological markers of extracellular matrix remodeling predict transplant-free survival in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. AIM: To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis. METHODS: Serum samples were available from 138 large-duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008-2012 and 52 ulcerative colitis patients (controls). The median follow-up time was 2.2 (range 0-4.3) years. Specific biomarkers of type III and V collagen formation (PRO-C3 and PRO-C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinase-1 and hyaluronic acid was assessed for comparison. RESULTS: All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P < 0.001). PRO-C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P < 0.001). Combining PRO-C3 and PRO-C5 the odds ratio for predicting transplant-free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11. CONCLUSIONS: Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO-C3 was identified as a potent prognostic marker and an independent predictor of transplant-free survival in primary sclerosing cholangitis.

The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both?

The mammalian mitochondrial genome (mtDNA) is a small double-stranded DNA molecule that is exclusively transmitted down the maternal line. Pathogenic mtDNA mutations are usually heteroplasmic, with a mixture of mutant and wild-type mtDNA within the same organism. A woman harbouring one of these mutations transmits a variable amount of mutant mtDNA to each offspring. This can result in a healthy child or an infant with a devastating and fatal neurological disorder. Understanding the biological basis of this uncertainty is one of the principal challenges facing scientists and clinicians in the field of mitochondrial genetics.

Cardiac manifestations in oxidative phosphorylation disorders of childhood.

OBJECTIVE: To determine the frequency, type, and severity of cardiac involvement in pediatric patients with oxidative phosphorylation (OXPHOS) disorders. STUDY DESIGN: Retrospective review of clinical and laboratory records of all patients with definitive OXPHOS disorders diagnosed and treated at the Royal Children's Hospital in Melbourne between 1984 and 2005. RESULTS: Of a total of 89 patients (male:female ratio 1.5:1) 29 (33%) had cardiac involvement: 9 as presenting symptoms, 9 developing on follow-up, and 11 with subclinical cardiac findings. Leigh or Leigh-like syndrome and complex I and combined complex I, III, and IV deficiencies were the most common clinical and laboratory diagnoses, respectively. Clinically symptomatic patients had hypertrophic cardiomyopathy (5 patients), dilated cardiomyopathy (4 patients), combined ventricular hypertrophy and systolic dysfunction (3 patients), and left ventricular noncompaction (3 patients) at first assessment. A change in the type of cardiomyopathy was noted on follow-up in 2 patients. Conduction and rhythm abnormalities were present in 7 symptomatic patients. CONCLUSIONS: Cardiac assessment in children with OXPHOS disorders may reveal subclinical abnormalities of cardiac function. Patients who present with primary cardiac features have a poor prognosis. OXPHOS disorders should be considered in the differential diagnosis of children presenting with otherwise unexplained cardiomyopathy.

Incidence and characterization of serum transaminases elevations in pegylated interferon and ribavirin treated patients with chronic hepatitis C.

BACKGROUND: A virological response to pegylated-interferon and ribavirin is typically associated with a prompt fall in serum transaminases. For some patients, transaminases rise during treatment. AIM: To assess the frequency and define factors associated with elevations of serum transaminases. METHODS: A total of 169 treated patients were studied. Transaminase elevations were graded by WHO criteria - grade 0: no value > baseline, grade 1: 1-2x baseline, grade 2: 2.1-5x baseline, grade 3: >5x, grade 4: any rise with evidence of liver failure. Results 60/169 (35%) patients experienced transaminase elevations: 52 grade 1, 6 grade 2, 1 grade 3, 1 grade 4. Overall, end of treatment response and sustained virological response rates were 72% and 55%. Lower rates were observed in the grade 1 elevation group (63% and 40%) compared with patients with grade 0 (79% and 65%) and grade > or =2 elevations (85% and 71%). Grade 1 elevations tended to occur earlier during treatment than grade > or =2 elevations. Transaminase elevations were associated with greater pre-treatment body weight (P = 0.006), steatosis (P = 0.008) and poorer sustained virological response rates (P = 0.007). CONCLUSIONS: Transaminase elevations during treatment of chronic Hepatitis C virus with pegylated interferon and ribavirin are common but rarely severe. Mild rises may reflect ongoing viral activity in treatment non-responders. More significant rises are frequently observed despite a virological response, and may be because of an immuno-modulating effect of interferon in susceptible patients.