Hepatitis: Krawitt EL

Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Büschenfelde KH, Zeniya M. · Institute of Liver Studies, King's College Hospital, London, UK. · J Hepatol. · Pubmed #10580593 No free full text.

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Krawitt EL. · Department of Medicine, University of Vermont, Given C-246 Burlington, Vermont 05405-0068, USA. · World J Gastroenterol. · Pubmed #18528927 links to  free full text

Abstract: Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology which can progress to cirrhosis. Its clinical manifestations are highly variable and sometimes follow a fluctuating course. Diagnosis is based on characteristic histologic, clinical, biochemical and serological findings. Anti-inflammatory/immunosuppressive treatment frequently induces remission but long-term maintenance therapy is often required. Liver transplantation is generally successful in patients with decompensated cirrhosis unresponsive to or intolerant of medical therapy.

Krawitt EL. · Department of Medicine, University of Vermont, Burlington, VT 05405-0068, USA. · N Engl J Med. · Pubmed #16394302 No free full text.

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Czaja AJ, Bianchi FB, Carpenter HA, Krawitt EL, Lohse AW, Manns MP, McFarlane IG, Mieli-Vergani G, Toda G, Vergani D, Vierling J, Zeniya M. · Mayo Clinic College of Medicine, Division of Gastroenterology and Hepatology, Rochester, MN 55905, USA. · Hepatology. · Pubmed #15690485 No free full text.

Abstract: New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The assessment of new front-line and salvage therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic criteria and treatment regimens for children required codification, and pharmacokinetic studies were encouraged to develop optimal dosing schedules based on therapeutic ranges. Collaborative efforts were proposed to help understand racial, geographical, and genetic factors affecting outcome and to establish definitions and therapies for variant syndromes and graft dysfunction after transplantation. The development of experimental animal models was deemed essential for the study of site-specific molecular interventions, and gene therapy was endorsed as a means of bolstering reparative processes. In conclusion, evolving pharmacological and technical advances promise to improve the treatment of autoimmune hepatitis, and investigations of these advances are timely, feasible, and necessary.

Krawitt EL, Ashikaga T, Gordon SR, Ferrentino N, Ray MA, Lidofsky SD, Anonymous00047. · Department of Medicine, University of Vermont, Burlington, VT, USA. · J Hepatol. · Pubmed #16082735 No free full text.

Abstract: BACKGROUND/AIMS: Treatment regimens with pegylated interferons have yielded improved response rates, compared with conventional interferon-based regimens, for chronic hepatitis C. However, little is known about the utility of such regimens for individuals who failed to respond to prior conventional interferon-based treatment. METHODS: 182 patients who had previously failed to eliminate circulating hepatitis C virus 24 weeks after completion of a multi-week course of either interferon monotherapy or interferon in combination with ribavirin were treated with peginterferon alfa-2b weekly and ribavirin daily for 48 weeks. RESULTS: The sustained viral response, was 20% (23/116) in previous non-responders and 55% (36/66) in previous relapsers (P<0.001). In previous non-responders, the sustained viral response in those with viral genotype 1 was 17% (19/109) compared to 57% (4/7) in those with genotypes 2 and 3 (P=0.03). In previous relapsers, the sustained viral response in those with viral genotype 1 was 53% (26/49) compared to 59% (10/17) with genotypes 2 and 3 (P=0.78). CONCLUSIONS: The response to pegylated interferon and ribavirin in previous non-responders with genotypes 2 and 3 and in prior relapsers with chronic hepatitis C is comparable to overall sustained viral response rates seen in previously untreated patients.

Jensen DM, Krawitt EL, Keeffe EB, Hollinger FB, James SP, Mullen K, Everson GT, Hoefs JC, Fromm H, Black M, Foust RT, Pimstone NR, Heathcote EJ, Albert D. · Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA. · Am J Gastroenterol. · Pubmed #10606323 No free full text.

Abstract: OBJECTIVE: The effect of baseline viral concentration on response was assessed as part of a multicenter phase 3 trial evaluating the safety and efficacy of CIFN therapy for chronic HCV infection. METHODS: Patients (n = 472) received either CIFN 9 microg or IFN alpha-2b 3 MU subcutaneously t.i.w. for 24 wk, followed by 24 wk of observation. RESULTS: Efficacy was assessed by the percentage of patients who achieved normal ALT values or undetectable HCV RNA values (using RT-PCR with a sensitivity of 100 copies/ml). There was a clear relationship between baseline viral concentration and either ALT or HCV RNA response; patients with lower titer HCV RNA had better response rates. End-of-treatment HCV RNA responses were better for patients with low viral concentrations treated with CIFN (51%) than for patients treated with IFN a-2b (31%) (p = 0.03). ALT responses in patients with low viral concentrations were 60% for CIFN-treated patients and 27% for IFN alpha-2b-treated patients (p < 0.01) at the end of treatment. Patients with high titer HCV RNA were more likely to have a sustained HCV RNA response after treatment with CIFN 9 microg, compared with those treated with IFN alpha-2b (7% vs 0%, p = 0.03). CONCLUSIONS: Both genotype and baseline viral concentration were independent factors that affected response to interferon.

Cheng R, Barton JC, Morrison ED, Phatak PD, Krawitt EL, Gordon SC, Kowdley KV. · Department of Medicine, University of Washington, Seattle, WA, USA. · J Clin Gastroenterol. · Pubmed #19359997 No free full text.

Abstract: OBJECTIVE: There are limited data comparing hepatic phenotype among hemochromatosis patients with different HFE genotypes. The goal of this study was to compare hepatic histopathologic features and hepatic iron concentration (HIC) among patients with phenotypic hemochromatosis and different HFE genotypes. METHODS: We studied 182 US patients with phenotypic hemochromatosis. Degree of hepatic fibrosis, pattern of iron deposition, presence of steatosis or necroinflammation, and HIC were compared among different HFE genotypes. RESULTS: C282Y/H63D compound heterozygotes and patients with HFE genotypes other than C282Y/C282Y were more likely to have stainable Kupffer cell iron (31.1% vs. 9.5%; P=0.02), portal or lobular inflammation (28.9% vs. 15.6%; P=0.03), and steatosis (33.3% vs. 10.2%; P<0.01) on liver biopsy than C282Y homozygotes. Mean log10 HIC (P<0.05) and log10 ferritin (P<0.05) were higher among C282Y homozygotes than in patients with other HFE genotypes. In a logistic regression analysis using age, sex, HFE genotype, log10 ferritin, and log10 HIC as independent variables, log10 serum ferritin (P=0.0008), male sex (P=0.0086), and log10 HIC (P=0.047), but not HFE genotype (P=0.0554) were independently associated with presence or absence of advanced hepatic fibrosis. CONCLUSIONS: C282Y/H63D compound heterozygotes and other non-C282Y homozygotes which express the hepatic hemochromatosis phenotype frequently have evidence of steatosis or chronic hepatitis and lower body iron stores than C282Y homozygotes. These data suggest that presence of concomitant liver disease may explain expression of the hemochromatosis phenotype among non-C282Y homozygotes. Increased age, HIC, and ferritin are associated with advanced hepatic fibrosis, regardless of HFE genotype.

Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW, Anonymous00035. · Department of Medicine, University Medical Centre Hamburg Eppendorf, Germany. · Hepatology. · Pubmed #18537184 No free full text.

Abstract: Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff > or =6) and 81% sensitivity and 99% specificity (cutoff > or =7) in the validation set. CONCLUSION: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher.

Krawitt EL, Gordon SR, Grace ND, Ashikaga T, Ray MA, Palmer M, Yarze JC, Moskowitz S, Anonymous00459. · Department of Medicine, University of Vermont, Burlington, Vermont, and Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. · Am J Gastroenterol. · Pubmed #16771948 No free full text.

Abstract: PURPOSE: A prospective randomized trial was undertaken to test the efficacy of low and standard doses of pegylated interferon alpha-2b in combination with ribavirin for the initial treatment of chronic hepatitis C. By nature of its design the study also provided data on response to therapy over a spectrum of doses of both pegylated interferon alpha-2b and ribavirin calculated on a body weight basis. SUBJECTS AND METHODS: Fifty micrograms of pegylated interferon alpha-2b or 100 microg for patients weighing<75 kg or 150 microg for patients>or=75 kg were administered weekly with 1000 mg ribavirin daily for 48 wk if serum hepatitis C virus (HCV) RNA was undetectable after the first 24 wk of therapy. RESULTS: Overall sustained viral response (SVR) was 45% for standard dose and 33% for low dose, p=0.02. For genotypes 2 and 3 SVR was 65% for standard dose, and 56% for low dose, p=0.51. For genotype 1 SVR was 38% for standard dose, and 24% for low dose, p=0.03. For genotype 1 patients whose doses exceeded the 1-2-5 threshold, that is >or=1.25 microg/kg body weight pegylated interferon alpha-2b weekly and >or=12.5 mg/kg body weight ribavirin daily, SVR was 51%. CONCLUSION: The results of this study underscore the importance of adequate dosing of ribavirin as well as pegylated interferons in achieving an SVR when treating genotype 1 chronic hepatitis C patients with combination therapy.

Skripenova S, Trainer TD, Krawitt EL, Blaszyk H. · Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA. · J Clin Pathol. · Pubmed #16698951 No free full text.

Abstract: BACKGROUND: Grading and staging of liver biopsies in patients with chronic hepatitis remains an inexact "gold standard" that is influenced by variabilities in scoring systems, sampling, observer agreement and expertise. Spatial disease variability relative to markers of the adequacy of biopsy has not been studied previously. METHODS: Paired liver biopsy specimens were obtained from the right and left hepatic lobes of 60 patients with chronic hepatitis C. Histological grade and disease stage were assessed according to the Ludwig scoring system, and scores were evaluated in relation to differences in size and number of portal tracts in all paired samples. RESULTS: The relative difference (%) in aggregate biopsy size and number of portal tracts was similar between paired samples with and without a difference in grade. Paired samples with a difference in stage showed a larger relative difference in biopsy size (p = 0.09) and in the number of portal tracts (p = 0.016). CONCLUSIONS: Our study shows a difference of one grade or one stage in 30% of paired liver biopsies, due to a combination of sampling variability and observer variability. Acknowledgment of "built-in" variability in grading and staging chronic hepatitis C by both clinicians and pathologists is essential for managing the individual patient with chronic hepatitis C.

Pratt DS, Trainer TD, Krawitt EL. · Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. · Clin Gastroenterol Hepatol. · Pubmed #16234035 No free full text.

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Fukagawa NK, Liang P, Li M, Ashikaga T, Reddy KR, Krawitt EL. · Department of Medicine , University of Vermont College of Medicine, Burlington 05405-0068, USA. · Dig Dis Sci. · Pubmed #11680579 No free full text.

Abstract: Autoimmune hepatitis is associated with genes located in the major histocompatibility complex. The search for genes at other loci that may play a role in disease susceptibility and/or severity is an area of active investigation in autoimmune liver diseases. Genes for glutathione-S-transferases, enzymes that are widely distributed and collectively metabolize carcinogens, pollutants, drugs, and a broad spectrum of harmful, foreign compounds have been associated with liver disease. The objective of this study was to search for a relationship between the glutathione-S-transferase Ml null genotype and autoimmune hepatitis using polymerase chain reaction analysis. The findings indicate that the frequency of the null genotype is not increased in patients with autoimmune hepatitis when compared to control subjects. These results coupled with similar ones in primary biliary cirrhosis do not support a role for this mutation in autoimmune liver disease.

Cedar MA, Zancosky KL, Oliva LA, Molloy PJ, Weissgold DJ, Krawitt EL. · No affiliation provided · Am J Gastroenterol. · Pubmed #17958775 No free full text.

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Krawitt EL. · No affiliation provided · J Hepatol. · Pubmed #15519668 No free full text.

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Fine GD, Trainer TD, Krawitt EL. · No affiliation provided · Am J Gastroenterol. · Pubmed #15128376 No free full text.

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Nietsch HH, Libman BS, Pansze TW, Eicher JN, Reeves JR, Krawitt EL. · No affiliation provided · Am J Gastroenterol. · Pubmed #11051393 No free full text.

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Krawitt EL. · No affiliation provided · Ann Intern Med. · Pubmed #10577318 links to  free full text

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