Bettina E. Hansen

Improved Prognosis of Patients With Primary Biliary Cirrhosis That Have a Biochemical Response to Ursodeoxycholic Acid

BACKGROUND & AIMSnUrsodeoxycholic acid (UDCA) improves laboratory liver test results in patients with primary biliary cirrhosis (PBC). Few studies have assessed the prognostic significance of biochemical data collected following UDCA treatment. We performed a prospective multicenter study of patients with PBC treated with UDCA to compare prognosis with biochemical response.nnnMETHODSnPBC was classified as early (pretreatment bilirubin and albumin levels normal), moderately advanced (one level abnormal), or advanced (both levels abnormal). Biochemical response was defined as proposed by Pares (decrease in alkaline phosphatase [ALP] level>40% of baseline level or normal level), Corpechot (ALP level<3-fold the upper limit of normal [ULN], aspartate aminotransferase level<2-fold the ULN, bilirubin level<1-fold the ULN), and our group (Rotterdam; normalization of abnormal bilirubin and/or albumin levels).nnnRESULTSnThe study included 375 patients, and median follow-up time was 9.7 (range, 1.0-17.3) years. The prognosis for early PBC was comparable with that of the Dutch population and better than predicted by the Mayo risk score. Survival of responders was better than that of nonresponders, according to Corpechot and Rotterdam criteria (P<.001). Prognosis of early PBC was comparable for responders and nonresponders; prognosis of responders was significantly better in those with (moderately) advanced disease.nnnCONCLUSIONSnPrognosis for UDCA-treated patients with early PBC is comparable to that of the general population. Survival of those with advanced PBC with biochemical response to UDCA is significantly better than for nonresponders. Thus, UDCA may be of benefit irrespective of the stage of disease. Prognostic information, based on bilirubin and albumin levels, is superior to that provided by ALP levels.

A replicon-based bioassay for the measurement of interferons in patients with chronic hepatitis C

Overall treatment results of chronic hepatitis C have improved markedly with the introduction of pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin combination therapy. However, cure rates in the most common genotype 1 infection are still unsatisfactory. IFN-alpha dose-response studies on viral kinetics suggest that inadequate dosing might be a key factor but drug levels have hardly been tested, which is in part due to difficulties in measuring this cytokine in patient samples. We have shown recently that hepatitis C virus (HCV) replicons are highly sensitive to IFN-alpha. In this report we tested whether the replicon system could be used as a sensitive bioassay to determine the amount of biologically active IFN-alpha in serum or heparinized plasma of patients under therapy. To facilitate the measurements, a stably replicating subgenomic HCV RNA was developed that carries the gene encoding the firefly luciferase. Dose response studies with IFN-alpha demonstrate that the amount of expressed luciferase directly correlates with the level of HCV replication. By using this cell-based assay, serum samples of HCV patients treated with different types and doses of IFN-alpha were analyzed in parallel to IFN-alpha standards made by serial dilutions of the same type of IFN-alpha the patient was treated with. Based on nonlinear logistic models serum concentrations corresponding to 1.3-19 U/ml were determined in patients under standard or high dose IFN-alpha therapy, and from 3.8 to 4.1 ng/ml in patients treated with PEG IFN-alpha. In conclusion, the HCV-replicon based bioassay allows determining the levels of biologically active IFN-alpha in serum and heparinized plasma of patients under treatment.

γ‐Glutamyltransferase and rapid virological response as predictors of successful treatment with experimental or standard peginterferon‐α‐2b in chronic hepatitis C non‐responders

Background: High‐dose peginterferon‐α (PegIFN‐α) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non‐responders, although a higher and a longer dosing of PegIFN‐α may intensify side effects.

Long-term effects of treatment and response in patients with chronic hepatitis C on quality of life. An international, multicenter, randomized, controlled study

BackgroundHepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study).MethodsThe Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128).ResultsAt baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL.ConclusionsMain determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.

Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008

BackgroundA decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.MethodsAnalysis of PBC transplant data of the Dutch Organ Transplant Registry during the period 1988-2008, including both absolute and proportional numbers. The indication for LTX was categorized as liver failure, hepatocellular carcinoma or poor quality of life (severe fatigue or pruritus). Data were analysed for two decades: 1.1.1988-31.12.1997 (1st) and 1.1.1998-31.12.2007 (2nd). The severity of disease was quantified using MELD scores. To fit lines which show trends over time we applied a linear regression model.ResultsA total of 110 patients (87% women) was placed on the waiting list. 105 patients were transplanted (1st: 61, 2nd: 44), 5 (5%) died while listed. The absolute annual number of LTX for PBC slightly decreased during the 20 year period, the proportional number decreased significantly. At the time of LTX the mean age was 53.6 yrs. (1st: 53.4, 2nd: 53.8), the mean MELD score 13.9 (1st:14.5, 2nd:13.0). The median interval from diagnosis to LTX was 90.5 months (1st:86.5, 2nd: 93.5). 69% of patients was treated with UDCA (1st 38%, 2nd 82%).ConclusionsOver the past 20 years the absolute number of LTX for PBC in the Netherlands showed a tendency to decrease whereas the proportional decrease was significant. There was a trend over time toward earlier transplantation.

Immunoglobulin G4-related prostatitis: A case-control study focusing on clinical and pathologic characteristics

OBJECTIVEnTo evaluate the occurrence and histopathologic characteristics of immunoglobulin G4 (IgG4)-related prostatic involvement in patients diagnosed with autoimmune pancreatitis.nnnMETHODSnNine cases of IgG4-related prostatitis were identified among 117 men in the autoimmune pancreatitis and IgG4-associated cholangitis patient databases in 2 tertiary hospitals. Clinical information was retrieved, and available prostatic tissue samples and 18 prostatitis control samples were evaluated for characteristic IgG4-related disease (IgG4-RD) features: maximum number of IgG4-positive cells per high-power field; dense lymphoplasmacytic infiltrate; fibrosis, arranged at least focally in a storiform pattern; phlebitis with or without obliteration of the lumen; and increased number of eosinophils.nnnRESULTSnThe aspecific sign of urine retention was commonly present in IgG4-RD patients with prostatic involvement. In these patients with IgG4-related prostatitis, the median number of IgG4-positive cells in prostatic tissue was 150 (interquartile range, 20-150) per high-power field compared with a median of 3 (interquartile range, 1-11) in control patients (Pxa0= .008). Dense lymphoplasmacytic infiltrate was observed in most (86% in cases and 72% in control patients) tissue samples independent of the underlying cause of prostatitis. Fibrosis in at least a focally storiform pattern was seen rarely in both groups, and (obliterative) phlebitis was absent in all patients. Furthermore, eosinophil numbers were more often elevated in patients with IgG4-RD compared with controls (Pxa0<.001). In 2 cases, amelioration of the prostatitis symptoms on corticosteroid treatment was documented.nnnCONCLUSIONnProstatic involvement might not be rare in patients with pancreatic or biliary IgG4-RD. Clinicians should consider this disease entity in patients with IgG4-RD and prostatic symptoms.

Serum Level of Ca 19-9 Increases Ability of IgG4 Test to Distinguish Patients with Autoimmune Pancreatitis from Those with Pancreatic Carcinoma

BackgroundAutoimmune pancreatitis (AIP) is often difficult to distinguish from pancreatic carcinoma or other pancreatobiliary diseases. High serum levels of carbohydrate antigen 19-9 (Ca 19-9) are indicative of malignancies, whereas high levels of immunoglobulin (Ig)G4 (>1.4xa0g/l) are characteristic of AIP. We investigated whether serum levels of these proteins can differentiate between these diseases.MethodsWe measured levels of Ca 19-9 and IgG4 in serum samples from 33 patients with AIP, 53 with pancreatic carcinoma, and 145 with other pancreatobiliary disorders. We determined cut-off levels for each assay. Logistic regression analysis was used to evaluate combined data on Ca 19-9, IgG4, and bilirubin levels.ResultsLow levels of Ca 19-9 were independently associated with AIP, compared with pancreatic adenocarcinoma [odds ratio (OR) 0.28; 95xa0% confidence interval (CI) 0.13–0.59; pxa0=xa00.0001]. Using an upper level of 74xa0U/ml, the assay for Ca 19-9 identified patients with AIP with 73xa0% sensitivity and 74xa0% specificity. Using a lower level of 2.6xa0g/l, the assay for IgG4 identified these patients with 70xa0% sensitivity and 100xa0% specificity. Combining data, levels of Ca 19-9xa0<xa074xa0U/ml and IgG4xa0>xa01.0xa0g/l identified patients with AIP with 94xa0% sensitivity and 100xa0% specificity.ConclusionsPatients with AIP have lower levels of Ca 19-9 than those patients with pancreatic carcinoma. Measurement of either the Ca 19-9 or the IgG4 level alone are not accurate enough for diagnosis. However, the combination of Ca 19-9xa0<xa074xa0U/ml and IgG4xa0>xa01.0xa0g/l distinguishes patients with AIP from those patients with pancreatic carcinoma with 94xa0% sensitivity and 100xa0% specificity.

P1177 : Risk factors for hepatic decompensation in primary biliary cirrhosis - results of an international follow up study of 2326 patients

were independent variables related to ATX activity. In terms of HRQoL, serum ATX was associated with fatigue (r = 0.218; p =0.02) in PBC-40 as well as fatigue (r = 0.217; p =0.02), cognitive (r = 0.207; p =0.03) and emotional (r = 0.202; p =0.03) domains of the PBC27 questionnaire. No correlations were found with generic SF-36 domains, except for physical functioning (r = 0.204; p =0.03). Conclusions: In patients with PBC, serum ATX is not only associated with pruritus but may also be involved in impairment of further aspects of patients’ quality of life and liver dysfunction. Thus, ATX inhibitors could be of potential benefit not only in the treatment of pruritus but also other incapacitating symptoms related to chronic cholestasis.