Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are the most common symptomatic primary antibody deficiencies (PADs). Patients with PAD may develop severe liver disease as part of their immunodeficiency syndrome.1Ward C. Lucas M. Piris J. Collier J. Chapel H. Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia.Clin Exp Immunol. 2008; 153: 331-337Crossref PubMed Scopus (85) Google Scholar There has been a reluctance to perform liver transplantation (LTX) in these patients due to the risks associated with lifelong immunosuppression and fear of severe infections. Previously, iatrogenic chronic hepatitis C virus (HCV) infection was a leading cause of end-stage liver disease in patients with PAD and the lack of eradication of the virus after transplantation added to the reluctance to perform LTX in these patients.2Razvi S. Schneider L. Jonas M.M. Cunningham-Rundles C. Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency.Clin Immunol. 2001; 101: 284-288Crossref PubMed Scopus (47) Google Scholar We present our experiences of LTX in patients with PAD with an emphasis on complications and outcome. The information was retrieved from the patients' medical records and the Nordic Liver Transplant Registry. From 1993 to 2013, 6 patients (2 women), aged 19 to 62 years, with PAD (5 CVID, 1 XLA [diagnosis based on family history in brothers and uncles and of clinical manifestations before the age of 2 years]) underwent LTX at our center. Before LTX, all patients had recurrent bacterial airway infections, despite treatment with IgG and IgG levels within reference values, and bronchiectasis. All patients with CVID had splenomegaly and lymphadenopathy as part of their phenotype before developing liver failure. Other noninfectious complications included granulomatous inflammation (2 CVID), organ-specific autoimmune diseases (3 CVID), autoimmune cytopenias (3 CVID), and enteropathy (3 CVID). The 2 patients who underwent LTX in 1993 and 1998 had HCV infection (1 CVID, 1 XLA). The last 4 non–HCV-infected patients (4 CVID) had either definite or probable nodular regenerative hyperplasia (NRH) (Table I). The first 2 patients, transplanted in the 1990s, received immunosuppression with glucocorticoids combined with cyclosporine A or tacrolimus. The final 4 patients received immunosuppression consisting of glucocorticoids, tacrolimus, and mycophenolate. One patient received anti-IL2 receptor–blocking mAbs (basiliximab) as induction therapy (patient 4). The first 2 patients who underwent transplantation in 1993 and 1998 died 1.8 years and 0.1 year after LTX (Table II). Patient 1 died because of sepsis combined with a debilitating Cryptosporidium parvum infection and cytomegalovirus pneumonitis. Patient 2 died because of cerebral abscess by Aspergillus fumigatus while in liver failure due to HCV infection recurrence after LTX. Patient 1 was also diagnosed with acute cellular allograft rejection 8 months after LTX (mild rejection with a Banff rejection activity index of 4). The 4 patients transplanted between 2009 and 2013 are alive, with a median survival of 5 years (range, 3-7 years). All these patients experienced infections after LTX including symptomatic cytomegalovirus infections (n = 2), bacterial infections (n = 5, 2 with sepsis), parasitic infections (n = 2), and invasive fungal infections (n = 3). Patients 4 and 5, who underwent LTX because of hepatopulmonary syndrome, still have respiratory failure. One patient developed carcinoma in situ of the skin in 3 locations. Currently, 1 patient has normal biochemical liver parameters, while 3 have slightly elevated alkaline phosphatase and aspartate transaminase. None of the patients has clinical signs of liver failure.Table IClinical characteristics and liver disease in 6 patients with PAD before LTXPatientAge (y)SexPrimary immunodeficiencyCause of LTXHistology of native liverMELD∗MELD score: model of end-stage liver disease score (18). score at time of transplantation†Meld score based on conversion of prothrombin time to international normalized ratio.Year of transplantation119MCVIDHepatitis C – liver failureCirrhosis with portal and lobular inflammation with interphase activity, consistent with end-stage HCV infectionLoss of small intrahepatic bile ducts and lymphocyte-dominant cholangitis of larger bile ductsChronic cholecystitis with pyloric metaplasia16†Meld score based on conversion of prothrombin time to international normalized ratio.1993247MXLAHepatitis C – liver failureCirrhosis with portal and lobular inflammation with interphase activity, consistent with end-stage HCV infection11†Meld score based on conversion of prothrombin time to international normalized ratio.1998357FCVIDAcute portal vein thrombosis and liver failurePortal and septal fibrosis, nodular parenchyma suggestive of NRHMultifocal ischemic parenchymal necrosis and portal vein thrombosis212009454MCVIDRespiratory failure due to hepatopulmonary shuntingNRHPortal, centrilobular, and perisinusoidal fibrosisLymphocyte-dominant portal and lobular inflammationFocal circulatory changes with sinusoidal dilatation and hepatocyte injuryChronic cholecystitis82011562MCVIDRespiratory failure due to hepatopulmonary shuntingNRHPortal and lobular inflammation with parenchymal granulomas152011640FCVIDLiver failureNRHPortal and septal fibrosisPortal and lobular inflammation142013F, Female; M, male.∗ MELD score: model of end-stage liver disease score (18).† Meld score based on conversion of prothrombin time to international normalized ratio. Open table in a new tab Table IIComplications and survival after LTXPatientComplicationsSurvival (y)RejectionViral infectionBacterial infectionParasitic infectionFungal infectionMalignant or premalignant lesionsMiscellaneous1NoNoNoNoFatal A fumigatus brain abscessNoNone0.12YesCMV pneumoniaSepsis∗No species identified.Fatal C parvum infectionNoNoInflammation of upper GI tractAutolytic liver with portal fibrosis and bile stasis1.83NoNoRecurrent Clostridium difficile colitisRecurrent UTIS enteritis†Salmonella infection after trip to southeast Asia.PyelonephritisNoNoNoMonoclonal B cell of uncertain significance74NoUlcerative CMV disease of the GI tractS aureus pneumoniaC difficile colitisNoA fumigatus pneumoniaCarcinoma in situ of the skin in head, leg, and penis‡Classified as undifferentiated penile intraepithelial neoplasia.Bilateral lung emboliA-V malformations in lungs55NoNoBacterial pneumonia and sepsis∗No species identified.NoPCP pneumoniaCandida esophagitisNoModerate renal failureRespiratory failure56NoNoRecurrent bacterial vaginosisC parvum intestinal infectionNoNoColitisCytopenia of all 3 lineages of unknown cause – glucocorticoids sensitive3A-V, Arteriovenous; GI, gastrointestinal; PCP, Pneumocystis pneumonia; UTI, urinary tract infection.∗ No species identified.† Salmonella infection after trip to southeast Asia.‡ Classified as undifferentiated penile intraepithelial neoplasia. Open table in a new tab F, Female; M, male. A-V, Arteriovenous; GI, gastrointestinal; PCP, Pneumocystis pneumonia; UTI, urinary tract infection. Previous publications on LTX in PAD are summarized in Table E1 in this article's Online Repository at www.jacionline.org and have mostly been reported on pediatric and HCV-infected patients, with poor outcome. Changes in immunosuppressive drug regimens from the 1990s to 2009-2013 including lower doses of glucocorticoid will conceivably influence the outcome of LTX in PAD. A general improvement in results after LTX, regardless of diagnosis, has been reported3Fosby B. Melum E. Bjøro K. Bennet W. Rasmussen A. Andersen I.M. et al.Liver transplantation in the Nordic countries–an intention to treat and post-transplant analysis from the Nordic Liver Transplant Registry 1982–2013.Scand J Gastroenterol. 2015; 50: 797-808Crossref PubMed Scopus (55) Google Scholar and should be considered when interpreting older studies regarding LTX in patients with PAD. The switch of the major indication for LTX from chronic progressive HCV infection to idiopathic liver disease such as NRH may contribute to better outcome. All the 4 non–HCV-infected patients with PAD in our report had definite or probable NRH, which may in some patients with CVID lead to hepatitis and portal hypertension, resulting in ascites and liver failure. NRH was the indication for transplantation in 2 of our patients, while hepatopulmonary syndrome, which may be associated with NRH,4Park Y.W. Woo H. Jeong Y.Y. Lee J.H. Park J.J. Lee S.S. Association of nodular regenerative hyperplasia of the liver with porto-pulmonary hypertension in a patient with systemic lupus erythematosus.Lupus. 2006; 15: 686-688Crossref PubMed Scopus (10) Google Scholar was the main reason for LTX in 2 patients. The combination of PAD and LTX seemingly leads to uncommon opportunistic infections (C parvum, invasive aspergillosis) not usually seen in Norway in patients with CVID or after LTX.5Rodrigues F. Davies E.G. Harrison P. McLauchlin J. Karani J. Portmann B. et al.Liver disease in children with primary immunodeficiencies.J Pediatr. 2004; 145: 333-339Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 6Chen Y. Cameron A. Aspergillosis after liver transplantation in the context of common variable immunodeficiency: case report.Transpl Infect Dis. 2013; 15: 540-544Crossref PubMed Scopus (24) Google Scholar In Norway, fluconazole is used as antifungal prophylaxis after LTX. Because of our findings, we advise that the use of antifungal prophylaxis include drugs active against filamentous fungi in patients with PAD undergoing LTX. This is, to our knowledge, the largest report of LTX in PAD. Patients with PAD should be considered for LTX and not rejected on the basis of their immunodeficiency alone. Table E1Review of the literature on LTXs to patients with primary immunodeficiencySourcePatients: AgeImmunodeficiencyHepatitis CRejectionInfectionMiscellaneousOutcomeSmith et al,E1Smith M.S. David A. Webster B. Dhillon A.P. Dusheiko G. Boulton R. et al.Orthotopic liver transplantation for chronic hepatitis in two patients with common variable immunodeficiency.Gastroenterology. 1995; 108: 879-884Abstract Full Text PDF PubMed Scopus (40) Google Scholar 19951: 41 yCVIDYesYesSepsis, HCV recurrenceNoDead 23 mo after LTX2: 30 yCVIDNoYesPneumoniaNoDead 15 mo after LTXHadžić et al,E2Hadžić N. Pagliuca A. Rela M. Portmann B. Jones A. Veys P. et al.Correction of the hyper-IgM syndrome after liver and bone marrow transplantation.N Engl J Med. 2000; 342: 320-324Crossref PubMed Scopus (89) Google Scholar 20003: 18 yCD40L deficiencyNoMild GvHD after HSCTXNoHSCTX 34 d after LTXAlive 14 mo after LTXRazvi et al,E3Razvi S. Schneider L. Jonas M.M. Cunningham-Rundles C. Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency.Clin Immunol. 2001; 101: 284-288Crossref PubMed Scopus (53) Google Scholar 20014-9: 4 of 6> 21 yVarious PADsYes???4 of 6 patients diedGow et al,E4Gow P.J. Mutimer D. Successful outcome of liver transplantation in a patient with hepatitis C and common variable immune deficiency.Transpl Int. 2002; 15: 380-383Crossref PubMed Scopus (23) Google Scholar 200210: 43 yCVIDYesYesNoHCV recurrence, liver failureAlive 5 y follow-upRodrigues et al,E5Rodrigues F. Davies E.G. Harrison P. McLauchlin J. Karani J. Portmann B. et al.Liver disease in children with primary immunodeficiencies.J Pediatr. 2004; 145: 333-339Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar 200411: 13 yCIDNoChronic GvHDNoLTX 6 wk after HSCTXAlive 55 mo after LTX12: (0.8-17.9)CD40L deficiencyNoNoFatal C parvumLTX 2 mo after HSCTXDead13: (0.8-17.9)CVIDNoNoFatal C parvumNoDead14: (0.8-17.9)CD40L deficiencyNoNoFatal C parvumLTX × 2Dead 4 mo after LTXMurakawa et al,E6Murakawa Y. Miyagawa-Hayashino A. Ogura Y. Egawa H. Okamoto S. Soejima Y. et al.Liver transplantation for severe hepatitis in patients with common variable immunodeficiency.Pediatr Transplant. 2012; 16: E210-E216Crossref PubMed Scopus (19) Google Scholar 201215: 20 yCVIDNoYesNoLTX × 2Alive 2 y after LTX16: 9 yCVIDNo×5NoNoAlive 5 y after LTXChen et al,E7Chen Y. Cameron A. Aspergillosis after liver transplantation in the context of common variable immunodeficiency: case report.Transpl Infect Dis. 2013; 15: 540-544Crossref PubMed Scopus (35) Google Scholar 201317: 17 yCVIDNoNoFatal aspergillosisNoDead 33 d after LTXMontalti et al,E8Montalti R. Mocchegiani F. Vincenzi P. Svegliati B.G. Nicolini D. Vivarelli M. Liver transplantation in patients with common variable immunodeficiency: a report of two cases.Ann Transplant. 2014; 19: 541-544Crossref PubMed Scopus (15) Google Scholar 201418: 21 yCVIDYesNoHCV recurrenceAnastomotic biliary stricture, Roux-en-YAlive 3.5 y after LTX19: 53 yCVIDNo, HBVYesCMV reactivationNoAlive at 1 y after LTXCID, Combined immunodeficiency; GvHD, graft-versus-host disease; HBV, hepatitis B virus; HSCTX, hematopoietic stem cell transplantation. Open table in a new tab CID, Combined immunodeficiency; GvHD, graft-versus-host disease; HBV, hepatitis B virus; HSCTX, hematopoietic stem cell transplantation.

The aim of this study was to determine in patients with HCV genotype 2 or 3 the performance at week 4 of two assays with different sensitivities for HCV RNA detection, for the prediction of SVR and stratification for treatment duration (14 and 24 weeks). Recruitment was from two trials comparing 14 and 24 weeks treatment to patients with rapid virological response (RVR) (n = 550). RVR was originally defined as HCV RNA <50 IU/ml at week 4. Patients with an available frozen plasma sample drawn at week 4 and with follow-up data week 24 post-treatment were included (n = 429). HCV-RNA was prospectively measured with COBAS Amplicor V2, Roche (CA) (lower detection limit 50 IU/ml) and retrospectively assessed with VERSANT HCV-RNA Qualitative Assay, Siemens (TMA) (lower limit detection 10 IU/ml). Genotype 3 was present in 80% and genotype 2 in 20%. A SVR was achieved in 82%. At week 4 HCV-RNA was undetectable in 74.8% and 63% of serum samples tested with CA and TMA, respectively. CA undetectable/TMA positive was observed in 61/341 (18%) of the samples. In genotype 3 patients a relapse was seen in 9% of the patients with both CA and TMA undetectable and in 25% of the patients who were CA undetectable/TMA positive (p = 0.006). In patients allocated to 14 weeks treatment a relapse was observed in 11% of TMA undetectable patients and 26% of TMA positive (p = 0.031). In genotype 2 patients treated for 14 weeks relapse was observed in 6% of the patients with both CA and TMA undetectable week 4. Assays with high sensitivity for HCV RNA identifies patients at week 4 with high risk of virological relapse. We recommend that patients with genotype 3 and detectable HCV RNA at levels below 50 IU/ml do not receive truncated therapy with pegIFN and ribavirin.

Aim and background. The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. Materials and methods. The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. Results. Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five-and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. Conclusion. The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Background and aims: Curative treatment of hepatocellular carcinoma (HCC) is dependent on early diagnosis. Surveillance of patients at high risk for HCC is a key determinant to achieve this goal, but may be an underutilized tool. The aim of this study was to determine the rate of pre-diagnosis surveillance in patients with HCC in a large population-based cohort and to assess to what extent cirrhosis was known prior to the diagnosis of HCC.Methods: All patients diagnosed with HCC during 2000-2009 in The South-Eastern Regional Health Authority, representing 56% of the Norwegian population, were identified from The National Cancer Registry and the medical records were reviewed.Results: Fifteen out of 486 patients (3%) were diagnosed by surveillance. Potential curative treatment was offered to 58% of the patients who underwent surveillance as opposed to 15% in the non-surveillance group. Only age <= 65 years was an independent predictor of screening in a multivariate model. Almost two thirds of the patients with cirrhosis were unrecognized prior to the HCC diagnosis. Two hundred and fourteen patients (44%) were non-cirrhotics.Conclusion: Regular HCC surveillance in at-risk populations is virtually not applied in Norway and this may contribute to inferior overall survival. Failure to recognize cirrhosis and a high rate of HCC in non-cirrhotic patients will be limiting factors for the overall effectiveness of a potential surveillance program. (C) 2014 Elsevier Ltd. All rights reserved.

Objectives Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response. Methods Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon &agr;-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4. Results Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10−4, Prs7270101=0.0036, PITPase deficiency variable =6.3×10−22). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16–0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22). Conclusion We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.

Aims:We aimed to confirm the association of genetic variation at the ITPA locus and protection from RBV-induced hemolysis along with the need for RBV dose reduction and hence the possible impact on RVR and SVR.Methods: Patients were recruited from two previously published Scandinavian trials (n = 550) comparing the effect of pegINF-alfa-2B and weight-based RBV (800-1400 mg/day) in genotype 2 or 3 patients.DNA was extracted from 471 samples and genotyped for rs1127354 and rs7270101 with Taqman assays.The composite ITPase deficiency variable was graded according to activity.Multivariate linear regression was used for analysis of quantitative Hb reduction and multivariate Cox-regression for time-dependent RBV dose reduction.Results: Eighty percent of the patients were infected with genotype 3 and 61% were males.Mean Hb-reduction at week 4 was 1.32 g/dL.In the univariate analysis both SNPs (P rs1127354 = 2.9×10 -4 , P rs7270101 = 2.9×10 -5 ) and the composite ITPase deficiency variable (P = 7.3×10 -20 ) were associated with quantitative Hb reduction at week 4.These associations remained significant in a multivariate analysis adjusting for other predictors of anemia.(P = 7.5×10 -6 and P = 3.7×10 -5 and P = 1.2×10 -22 ).Hb at baseline was the only significant covariable predicting anemia at week 4 (P = 3.2×10 -13 ).In multivariate Cox-regression there was a significant association between the ITPase deficiency variable and RBV dose reduction throughout the treatment course (HR 0.53, P = 0.039).There was no significant association between the SNPs and RVR (P 1127354 = 0.34, P 7270101 = 0.81) or SVR (P 1127354 = 0.52.P 7270101 = 0.34). Conclusion:This study of G2/G3 patients confirms a strong and significant association between rs1127354, rs7270101 or the composite ITPase variable and quantitative hemoglobin reduction at week 4.In addition we found a significant association between timedependent RBV reduction although it did not influence RVR or SVR.

CONTEXT:Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western and non-Western countries, but its pathogenesis is not fully understood.OBJECTIVE:Based on the role of nicotinamide phosphoribosyltransferase (NAMPT) in fat and glucose metabolism and cell survival, we hypothesized a role for NAMPT/visfatin in the pathogenesis of NAFLD-related disease.DESIGN AND SETTING:We conducted clinical studies at a referral medical center in well-characterized NAFLD patients (n = 58) and healthy controls (n = 27). In addition we performed experimental in vitro studies in hepatocytes.MAIN OUTCOME MEASURES:We examined 1) the hepatic and systemic expression of NAMPT/visfatin in patients with NAFLD and control subjects, 2) the hepatic regulation of NAMPT/visfatin, and 3) the effect of NAMPT/visfatin on hepatocyte apoptosis.RESULTS:Our main findings were as follows. 1) Patients with NAFLD had decreased NAMPT/visfatin expression both systemically in serum and within the hepatic tissue, with no difference between simple steatosis and nonalcoholic steatohepatitis. 2) By studying the hepatic regulation of NAMPT/visfatin in wild-type and peroxisome proliferators-activated receptor (PPAR)alpha(-/-) mice as well as in hepatocytes, we showed that PPARalpha activation and glucose may be involved in the down-regulation of hepatic NAMPT/visfatin expression in NAFLD. 4) Within the liver, NAMPT/visfatin was located to hepatocytes, and our in vitro studies showed that NAMPT/visfatin exerts antiapoptotic effects in these cells, involving enzymatic synthesis of nicotinamide adenine dinucleotide.CONCLUSION:Based on these findings, we suggest a role for decreased NAMPT/visfatin levels in hepatocyte apoptosis in NAFLD-related disease.

Polymorphisms near the IL28B gene, which code for interferon (IFN)‐λ3, predict response to pegylated interferon‐α (PEG‐IFN) and ribavirin treatment in hepatitis C virus (HCV) genotype 1 infected patients. Follow‐up studies of the effect of IL28B gene in HCV non–genotype 1 infected patients have almost always used predominantly HCV genotype 2–infected or mixed genotype 2/3–infected cohorts with results partly conflicting with HCV genotype 1. We performed a retrospective analysis of 281 patients infected with HCV genotype 3 for association of response to therapy with IL28B polymorphisms. We found that the HCV genotype 1 responder genotypes at rs12979860 and rs8099917 did not associate with sustained virological response to PEG‐IFN/ribavirin therapy. However, the responder genotypes of both SNPs showed association with rapid viral response measured at 4 weeks (rs12979860, P = 3 × 10−5; rs8099917, P = 3 × 10−4). In multivariate analysis, age (<40 years), baseline viral load (<4 × 105 IU/mL) and the responder genotypes of SNPs rs12979860 or rs8099917 remained significant independent predictors of rapid viral response to therapy. Furthermore, we show that IL28B polymorphisms are associated with relapse in patients who achieve rapid viral response to PEG‐IFN/ribavirin therapy. The responder genotypes also showed association with markers of stage and activity of liver disease, namely high aspartate aminotransferase platelet ratio index (APRI, rs12979860, P = 0.018; rs8099917, not significant) and high alanine aminotransferase (ALT, rs12979860, P = 0.002; rs8099917, P = 0.001), in addition to a high baseline viral load (rs12979860, P = 1.4 × 10−5; rs8099917, P = 7.3 × 10−6). Conclusion: Polymorphisms near the IL28B gene show association with rapid viral response but not sustained viral response to PEG‐IFN/ribavirin therapy in HCV genotype 3‐infected patients. (HEPATOLOGY 2011;)

BACKGROUND In Norway, liver transplantation has been the treatment of choice for irreversible acute and chronic liver failure for 25 years. The aim of this article is to present a summary of the results obtained. MATERIAL AND METHODS All liver transplants performed in Norway in the period 25.02.84-31.12.08 have been reviewed retrospectively with respect to patient and donor epidemiology, survival and recurrence. RESULTS 651 transplants have been performed in this period. The annual number of transplants increased gradually up to the year 2000 (31), and more steeply afterwards - to 79 in 2008. Also the number of organ donations has increased and reached 98 (20 pr. million inh.) in 2008. 5-year patient survival was 53 % in the period 1984-1994. In the period 2001-2008, 1-year survival was 90 % and 5-year survival was 83 %. INTERPRETATION The gradual improvement of results should be interpreted in light of improvements within transplant surgery, medicine and anaesthesiology and the increased local experience due to the increasing number of transplants performed. The transplant centre at Rikshospitalet has developed into being among the largest of its kind within the Nordic Countries and the results compare well with the best international data.

OBJECTIVES:Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD).METHODS:Serum levels of activin A and its natural inhibitor, follistatin, were measured in patients with NAFLD (n=70) and in control subjects (n=30). Gene expression was quantified in liver biopsies obtained from patients with NAFLD (n=13) and controls (n=6). Effects of activin A were examined in Huh7 (human hepatoma cell line) hepatocytes.RESULTS:Patients with NAFLD had significantly elevated serum levels of activin A and follistatin compared with healthy controls. In patients with non-alcoholic steatohepatitis (NASH, n=38), there were particularly high levels of activin A that were significantly related to the degree of hepatic fibrosis. Liver biopsies from NAFLD patients showed a markedly increased activin A-follistatin mRNA ratio, indicating increased hepatic activin A activity. In hepatocytes, activin A enhanced the expression of collagen and TGF-beta(1), promoted matrix metalloproteinase activity, induced mitochondrial beta-oxidation, downregulated fatty acid (FA) synthase activity, promoted decreased weight percentage of saturated FAs, and altered the composition of polyunsaturated FAs.CONCLUSIONS:Our findings support the complex role of activin A in the pathogenesis of NAFLD, involving effects on fibrosis and lipid accumulation.

A. Mangia1, O. Dalgard2, N. Minerva3, H. Verbaan4, G. Scotto5, D. Bacca6, E. Agostinacchio7, K. Bjoro8, V. Carretta9, V. Piazzolla1, R. Cozzolongo10, M. Romano11, L. Mottola1, A. Andriulli12. 1Liver Unit, IRCCS ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo, Italy; 2Medical Department, Aker University Hospital, Oslo, Norway; 3Medical Department, Hospital, Canosa, Italy; 4Department of Surgery, Division of Gastroenterology and Hepatology, University Hospital, Malmoe, Sweden; 5Infectious Diseases Department, University Hospital, Foggia, 6Medical Department, Hospital, Casarano, 7Medical Department, ‘Santa Rita’ Hospital, Bari, Italy; 8Medical Department, RiksHospital, Oslo, Norway; 9Medical Department, Hospital, Venosa, 10Gastroenterology Department, IRCCS ‘S. De Bellis’, Castellana Grotte, 11Medical Department, ‘S. Pertini’ Hospital, Roma, 12Gastroenterology Department, IRCCS ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo, Italy E-mail: a.mangia@tin.it

Angiotensin Converting Enzyme (ACE) activity was measured in maternal and fetal blood samples from preeclamptic and normotensive pregnancies and in samples from non-pregnant women. The enzyme activity was found to be significantly higher in the hypertensive pregnancies. For all pregnancies the levels in the umbilical venous samples exceeded those in the arterial samples.The vascular production of prostacyclin and thromboxane was investigated by in vitro perfusion of umbilical arteries from these pregnancies. Both angiotensin I and II elicited significant changes in the production, giving an increased prostacyclin/thromboxane ratio. In the hypertensive pregnancies the arteries displayed a lower production rate, and the angiotensin-induced changes were smaller, especially those of angiotensin I.The results indicate that preeclampsia also involves circulatory changes in the fetus, and that the vascular angiotensin I-conversion might be reduced despite higher circulating activity of the converting enzyme.

In this issue of the Scandinavian Journal of Gastroenterology Becher & El-Serag present a systematic review on non-malignant complications in gastroesophageal reflux disease (GERD) [1]. Although de...

OBJECTIVE:The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease.MATERIAL AND METHODS:Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers.RESULTS:No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p<0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p<0.001), glucose (p=0.032) and on HbA1c (p=0.020).CONCLUSIONS:Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. (ClinicalTrials.gov number, NCT00303537).