Hepatitis: Neuberger J

Booth JC, O'Grady J, Neuberger J, Anonymous00102. · Department of Gastroenterology, Royal Berkshire Hospital, London Road, Reading RG5 5AN, UK. · Gut. · Pubmed #11413125 links to  free full text

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Mells G, Neuberger J. · No affiliation provided · Transplantation. · Pubmed #18580457 No free full text.

Abstract: Protocol liver allograft biopsies are liver biopsies carried out at specific time points according to predetermined guidelines, rather than in response to specific indications such as change in the patient's clinical status or biochemical tests. Use of protocol liver allograft biopsy has been declining over the last decade: an informal survey of 35 transplant units showed that whereas 65% of units undertake protocol biopsies for those grafted for Hepatitis C virus infection, only 25% do so for patients grafted for other indications. In this overview, we consider the arguments against and those in favor of liver biopsies in adult liver allograft recipients. Arguments against the use of protocol liver biopsies are that they biopsies put the patient are associated with a small risk of morbidity and mortality, are expensive, do not provide useful information and do not alter clinical practice. The estimated rate of major complications is 0.6% and the estimated mortality rate 0.02%. However, the argument in favor of protocol biopsies is that even when standard liver tests are normal, there is on-going inflammation in the graft which, if immunosuppression is not altered, will lead to progressive fibrosis, cirrhosis and even graft loss. Conversely, normal liver histology may allow for reduction in the immunosuppression and so lower the risk of the complications associated with immunosuppression. Currently available diagnostic techniques are not yet sufficiently sensitive or specific to provide an accurate reflection of the state of the graft and the presence or absence of graft damage. We conclude that, while there are no clear data showing that protocol liver allograft biopsies are cost effective and lead to improved patient and graft outcome, such biopsies still have a role in the management of the liver transplant recipient.

Mottershead M, Neuberger J. · No affiliation provided · Liver Transpl. · Pubmed #17600347 links to  free full text

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De Silva S, Neuberger J. · No affiliation provided · Liver Int. · Pubmed #16761993 No free full text.

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Oo YH, Neuberger J. · No affiliation provided · Liver Int. · Pubmed #15998416 No free full text.

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Schreuder TC, Hübscher SG, Neuberger J. · Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK. · Transpl Int. · Pubmed #18662365 No free full text.

Abstract: Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) may all recur after liver transplant. Diagnosis of rPBC is defined by histology; rAIH by serology, biochemistry and histology; rPSC by histology and/or imaging of the biliary tree and exclusion of other causes of nonanastomotic biliary strictures. Criteria for recurrent disease (RD) may differ from those used in similar disease in the native liver: frequent use of immunosuppressive therapy changes the pattern and natural history of RD and can co-exist with other transplant-related causes of graft damage. RD may occur in the presence of normal liver tests; the reported incidence will depend on the way in which diagnostic tests (especially protocol biopsies) are applied. The risk of RD increases with time, but does not correlate with the rate of graft loss. Treatment is largely unproven: ursodeoxycholic acid will improve serology and may slow progression of rPSC and rPBC; introduction or increased dose of corticosteroids may reduce progression of rAIH. Risk factors for rPBC include use of tacrolimus compared with cyclosporine; for rPSC include absence of colon peri-transplantation and for rAIH possible associations with some HLA haplotypes have been suggested.

Mottershead M, Neuberger J. · Queen Elizabeth Hospital, Birmingham B15 2TH, UK. · World J Gastroenterol. · Pubmed #18528936 links to  free full text

Abstract: Liver transplantation remains an effective treatment for those with end-stage disease and with intractable liver-related symptoms. The shortage of organs for transplantation has resulted in the need for rationing. A variety of approaches to selection and allocation have been developed and vary from country to country. The shortage of donors has meant that new approaches have to be adopted to make maximal use of the available organs; these include splitting grafts, use of extended criteria livers, livers from non-heart-beating donors and from living donors. Post transplantation, most patients will need life-long immunosuppression, although a small proportion can have immunosuppression successfully withdrawn. Newer immunosuppressive drugs and different strategies may allow a more targeted approach with a reduction in side-effects and so improve the patient and graft survival. For autoimmune diseases, transplantation is associated with significant improvement in the quality and length of life. Disease may recur after transplantation and may affect patient and graft survival.

Neuberger J. · Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK. · Liver Transpl. · Pubmed #16237682 links to  free full text

Abstract: 1. There are many causes of graft dysfunction post-liver transplant, but recurrent disease remains the most common cause. 2. Viral hepatitis, nonalcoholic and alcoholic steatohepatitis, and autoimmune diseases are the most common causes of recurrent disease. 3. Graft hepatitis occurs frequently and in many cases will not progress. 4. Cirrhosis in the absence of any identifiable cause develops in a minority. 5. Treatment is of the underlying cause but some, such as recurrent and de novo autoimmune hepatitis and recurrent primary sclerosing cholangitis may not respond well, and regraft may be required.

Neuberger J, Jothimani D. · Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. · Transplant Proc. · Pubmed #15919426 No free full text.

Abstract: The choice of immunosuppressive regime used after liver transplantation depends on many factors, which should include the effect of disease recurrence; recurrence of disease after liver transplantation may be affected by the degree and type of immunosuppression used and recurrent disease may affect patient and graft survival. For autoimmune diseases, recurrence of primary biliary cirrhosis develops sooner and more rapidly in those on tacrolimus compared with cyclosporine, but graft loss from recurrent disease is uncommon; recurrence rates of primary sclerosing cholangitis is unaffected by immunosuppressive regimes and recurrence of autoimmune hepatitis may be reduced by prescription of corticosteroids. Whether the immunosuppressive regime affects the pattern of hepatocellular carcinoma recurrence is uncertain. It is probable that the use of calcineurin inhibitor does not have a significant effect and inhibitors of TOR may have an anti-cancer effect, but this still has to be shown clinically. Most metabolic diseases are not affected by the choice of immunosuppression, although recurrence of sarcoidosis may be prevented by corticosteroids.

Neuberger J. · The Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. · Gut. · Pubmed #15082598 links to  free full text

This publication has no abstract.

Neuberger J. · Liver Unit, Queen Elizabeth Hospital, Birmingham, England. · Liver Transpl. · Pubmed #14586904 links to  free full text

Abstract: 1. Recurrence of hepatitis C virus (HCV) in the graft is associated with a reduced quality of life and worse graft survival. 2. Pretransplantation, the severity of HCV recurrence may be reduced by reducing the pretransplantation load, by avoiding the use of organs from older donors, and by reducing the ischemic times. The effect of split livers on recurrence rates is uncertain. 3. The optimal immunosuppression regime has not been established but a heavy induction regime and treatment for acute rejection are associated with more viral replication and more graft damage. 4. Presently, there is no convincing evidence for preemptive treatment of HCV. 5. There are many studies on the effect of interferon with and without ribavirin for the treatment of HCV hepatitis. However, few are prospective, randomized, and controlled. 6. The current best treatment is with pegylated interferon and ribavirin; the dose and duration of treatment need to be established. Side-effects of treatment are common and reduction/withdrawal is frequent, but the regime is cost-effective. 7. The role of newer treatments remains to be established.

Neuberger J. · Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom. · Semin Liver Dis. · Pubmed #12447709 No free full text.

Abstract: Autoimmune hepatitis (AIH) is a good indication for liver transplantation, with 5- and 10-year survival rates approaching 75%. Determining the timing for transplantation remains difficult because progression to end-stage disease may be difficult to predict. After transplantation, the patients are at risk of recurrent AIH. This syndrome is not well-characterized and requires clearer definition. Introduction of corticosteroids is not always associated with arrest of disease. De novo AIH may also develop in the allograft. Although there is usually a good response to the reintroduction of corticosteroids or greater immunosuppression, some patients develop graft failure. Patients grafted for AIH tend to be at higher risk for both acute and chronic rejection. Withdrawal of immunosuppression is unlikely to be achieved.

Neuberger J. · Queen Elizabeth Hospital, Birmingham, UK. · Liver Transpl Surg. · Pubmed #10431015 No free full text.

Abstract: Rejection of the liver allograft may be classified as massive hemorrhagic necrosis or acute and chronic rejection. Massive hemorrhagic necrosis is now rarely seen; it occurs within the first few days after transplantation and is associated with transplantation across the blood-type groups. Early acute rejection (within 28 days of transplantation) is usually of little clinical significance and responds well to additional immunosuppression, whereas later rejection is associated with a greater risk for progression to graft loss. The incidence of early, acute rejection is dependent on the immunosuppressive regimen used and will vary between 20% and 70%. Patients who undergo transplantation for hepatitis B viral infection and alcohol-related liver disease have a lower incidence of rejection compared with those who undergo transplantation for cholestatic diseases, such as primary sclerosing cholangitis and primary biliary cirrhosis. Other factors that influence the incidence of acute rejection include age, race of recipient, and preservation injury. The incidence of chronic rejection is declining; most centers report current rates of 4% to 8%, whereas in earlier series, rates of 15% to 20% were observed. The reasons for this decline are unknown, but may relate to better immunosuppression. Chronic rejection usually presents within the first year posttransplantation. The greatest risk factor for chronic rejection is transplantation for chronic rejection; other factors include indication (especially primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis); cytomegalovirus infection, and low levels of immune suppression.

Williamson LM, Llewelyn CA, Fisher NC, Allain JP, Bellamy MC, Baglin TP, Freeman J, Klinck JR, Ala FA, Smith N, Neuberger J, Wreghitt TG. · Division of Transfusion Medicine, University of Cambridge, UK. · Transfusion. · Pubmed #10604250 No free full text.

Abstract: BACKGROUND: Virus inactivation of pooled fresh-frozen plasma (FFP) by the solvent/detergent (SD) method results in a loss of approximately 20 percent of factor VIII. This study aimed to assess the efficacy of SD-treated plasma in correcting the coagulopathy associated with liver disease and liver transplantation. STUDY DESIGN AND METHODS: Forty-nine patients with coagulation deficits due to liver disease, who required FFP for invasive procedures or liver transplantation, were randomly assigned to receive either FFP or SD-treated plasma. Patients were assessed for side effects, correction of coagulopathy over 24 hours, and seroconversion for viral markers 6 to 18 months after treatment. RESULTS: In the liver disease group, equal correction of clotting factors and partial thromboplastin time was seen with FFP and SD-treated plasma, with a similar return to baseline values over 24 hours. There was greater correction of the International Normalised Ratio in patients receiving SD-treated plasma (p = 0.037), but this patient group had higher baseline values than recipients of FFP (p = 0.024). Liver transplant patients also showed equivalent correction of coagulopathy with the same dose of FFP and SD-treated plasma. The use of other blood components during transplantation was identical in the two treatment groups. No seroconversions were seen for HIV or hepatitis B or C virus. One patient who had received FFP seroconverted for human parvovirus B19. Apparent seroconversion for hepatitis A virus seen at 9 to 13 months in four other patients was probably due to detection of passively transferred antibodies, as later testing of these patients gave negative results. Minor side effects were rare in both groups. CONCLUSION: SD-treated plasma is an efficacious source of coagulation factors for patients with liver disease who are undergoing biopsy or transplantation. Assessment of seroconversion for viral markers in recipients of plasma-derived products and plasma components should include consideration of the possibility that passively transferred antibodies were detected.

Li KK, Neuberger J. · Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK. · Expert Rev Gastroenterol Hepatol. · Pubmed #19485808 No free full text.

Abstract: Recurrent disease after liver transplantation is well recognized and remains a potential cause of premature graft loss. The rates of recurrence are difficult to establish because of the lack of consistency in diagnostic criteria and approaches to diagnosis. Owing to the fact that recurrent parenchymal disease may occur in the presence of normal liver tests, those centers that use protocol biopsies will report greater rates of recurrence. It is important to recognize that rates of recurrence vary according to indication and show little correlation with rates of graft loss from recurrent disease. Recurrance rates are greatest for primary sclerosing cholangitis and autoimmune hepatitis, and low reccurrance rates are reported for alcoholic liver disease and recurrent primary biliary cirrhosis. The impact of recurrent nonalcoholic fatty liver disease is not yet clear. Patients and clinicians need to be aware of the possibility of recurrent disease in the differential diagnosis of abnormal liver tests, and management stategies may require alteration to reduce the impact of disease recurrence on outcome. Finally, an understanding of which diseases do recur after transplantation and identification of the risk factors may lead to a better understanding of the pathogenetic mechanisms of these conditions.

Day E, Best D, Sweeting R, Russell R, Webb K, Georgiou G, Neuberger J. · University of Birmingham Department of Psychiatry, Queen Elizabeth Psychiatric Hospital, Birmingham, UK. · Liver Transpl. · Pubmed #18975295 No free full text.

Abstract: Transplantation for alcoholic liver disease is becoming increasingly common, and with adequate screening, short- to medium-term outcomes are very good. However, while conducting a prospective study of the outcome of liver transplantation in Birmingham, United Kingdom, we observed that a research diagnosis of alcohol abuse or dependence was made in a number of cases in which no reference to alcohol problems had been made by the referring agency. This article explores the characteristics of these "missed" cases and highlights key patient characteristics that might prompt a more detailed assessment of alcohol consumption. Two hundred eight individuals completed the research interview, and 80 (39%) met Diagnostic and Statistical Manual of Mental Disorders IV criteria for a lifetime diagnosis of either alcohol abuse (n = 29) or dependence (n = 51). When the initial referral details were reviewed, the possibility of alcohol problems had not been raised in 10 (12.5%) of these cases. Hepatitis C was the most common primary diagnosis in the missed cases, but there was no difference between diagnosed and missed cases in terms of demographic factors, severity of liver disease, or the number or degree of lifetime problems associated with alcohol. However, members of the missed group were more likely to have drunk alcohol in the past 6 months and in a greater volume and were more likely to have used illicit drugs such as opiates, amphetamines, hallucinogens, and cannabis. These findings point to the need to take an adequate history of lifetime alcohol problems in all patients being considered for liver transplantation.

Rowe IA, Webb K, Gunson BK, Mehta N, Haque S, Neuberger J. · Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. · Transpl Int. · Pubmed #18225996 No free full text.

Abstract: Many diseases that cause liver failure may recur after transplantation. A retrospective analysis of the rate and cause of graft loss of 1840 consecutive adults receiving a primary liver transplant between 1982 and 2004 was performed to evaluate the rate of graft loss from disease recurrence. The risk of graft loss from recurrent disease was greatest, when compared to primary biliary cirrhosis (PBC), in those transplanted for hepatitis C virus (HCV) [hazard ratio (HR) 11.6; 95% confidence interval (CI) 5.1-26.6], primary sclerosing cholangitis (PSC) (HR 6.0; 95% CI 2.5-14.2) and autoimmune hepatitis (AIH) (HR 4.1; 95% CI 1.3-12.6). The overall risk of graft loss was also significantly greater in HCV (HR 2.1 vs. PBC; 95% CI 1.5-3.0), PSC (HR 1.6 vs. PBC; 95% CI 1.2-2.3) and AIH (HR 1.6; 95% CI 1.0-2.4) than in PBC. There was no statistically significant difference in the risk of graft loss because of recurrent disease, when compared with PBC, for patients transplanted for alcohol related liver disease, nonalcoholic steatohepatitis and fulminant hepatic failure. Disease recurrence is a significant cause of graft loss particularly in HCV, PSC and AIH. Recurrent disease, in part, explains the increased overall risk of graft loss in these groups.

Barber K, Blackwell J, Collett D, Neuberger J, Anonymous00096. · UK Transplant, Bristol, UK. · Gut. · Pubmed #17008365 No free full text.

Abstract: BACKGROUND: Liver transplantation is a very successful therapy for those with end stage disease. Although there are numerous data on patient and graft survival after liver transplantation, life expectancy and possible loss of life (compared with a normal matched population) in those who survive remains unknown. AIMS: To assess the life expectancy and life years lost of adult liver allograft recipients, compared with an age and sex matched UK population to provide patients with more information and to improve the use of a scarce resource. METHODS: Using the National Transplant Database held by UK Transplant, on over 3600 adult liver allograft recipients transplanted between 1985 and 2003, we analysed survival of all adults who survived more than six months after transplantation and compared survival after transplantation with national age and sex matched controls to assess life years lost. RESULTS: Estimated median survival time of the analysis cohort of 2702 adult liver allograft recipients was 22.2 years (95% confidence interval 19.3-25.6), with an estimated loss of seven life years compared with an age and sex matched population. CONCLUSIONS: Overall, female recipients have a longer life expectancy and lose fewer life years than male recipients. While younger recipients have a longer life expectancy, they also lose more life years. Those transplanted for cancer, hepatitis C virus infection, and alcoholic liver disease had the greatest loss of life years.

Kimura Y, Leung PS, Kenny TP, Van De Water J, Nishioka M, Giraud AS, Neuberger J, Benson G, Kaul R, Ansari AA, Coppel RL, Gershwin ME. · Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis 95616, USA. · Hepatology. · Pubmed #12395334 No free full text.

Abstract: Intestinal trefoil factor (ITF) promotes epithelial cell migration and mucosal restitution during inflammation. We used real-time quantitative PCR, in situ nucleic acid hybridization, and immunohistochemistry to study the expression of the ITF gene and protein expression in the liver of primary biliary cirrhosis (PBC) and controls. There were significantly higher levels of ITF messenger RNA (mRNA) in PBC liver compared with primary sclerosing cholangitis (PSC) (P <.05) or normal controls (P <.001) and also higher in hepatitis C virus (HCV) liver (P <.05) and cryptogenic cirrhosis (P <.01) compared with normal controls. However, only in PBC was there a significant difference between small (interlobular and bile ductules) and large (intrahepatic and septal) bile ducts. Using in situ hybridization, the highest levels of ITF gene expression were localized to the large bile ducts in PBC. This differential expression of ITF was also noted at the protein level. Thus, in PBC, although 92% of large bile ducts expressed the ITF protein, only 2% of small bile ducts (P <.0001) expressed ITF. In contrast, in control livers, 34% of large bile ducts and 13% of small bile ducts expressed ITF. ITF protein is absent in small bile ducts in all stages of PBC. In conclusion, the expression of ITF may play an important role in bile duct damage. In small bile ducts, ITF production in response to damage is absent, making such cells vulnerable to damage and providing a thesis for the selective loss of small, but not large, bile ducts in PBC.

Jones RJ, Lewis SJ, Smith JM, Neuberger J. · Department of Clinical Biochemistry, Selly Oak Hospital, Birmingham, UK. · J Hepatol. · Pubmed #10782921 No free full text.

Abstract: There are many causes of a low serum caeruloplasmin. Not only may this be a feature of Wilson's disease, but a low level may be found in association with chronic liver disease of any cause. We report here a case where undetectable serum caeruloplasmin was found during routine investigation of a woman with hepatitis C viral infection.