Mild Chronic Hepatitis Research Articles

Association between IFN-gamma+874 polymorphisms and the clinical outcomes of hepatitis B and/or hepatitis C virus infection.

To explore the association between polymorphisms of interferon-gamma gene intron 1 at position +874 (IFN-gamma+874) gene and the susceptibility of HBV and/or HCV infection with different clinical outcomes. IFN-gamma+874 gene SNP were detected in 277 subjects including 79 chronic HBV/HCV coinfections, 69 individuals only with HBV infection, 55 individuals only with HCV infection and 74 controls, by sequence specific primers-PCR (SSP-PCR). Hepatocellular injury as suggested by alanine aminotransferase (ALT) was detected by Beckman LX-20. The status of viral particles in serum was determined by RT-nPCR. The possible association of the polymorphism of IFN-gamma+874 with the susceptibility of HBV and/or HCV infection and the outcome of these infections were analyzed. (1) IFN-gamma+874 AA frequency in individuals with chronic HBV, HCV, HBV/HCV coinfections were significant higher than that in controls (chi(2) = 16.15, P = 0.01);OR (95%CI) of IFN-gamma+874 AA in chronic infection with HBV, HCV, HBV/HCV coinfections appeared to be 2.70 (1.24 - 5.92), 3.22 (1.43 - 7.25) and 4.02 (1.88 - 8.55) compared with +874 TA. No significant differences were found among HBV, HCV, HBV/HCV coinfections (chi(2) = 1.97, P = 0.73). There were no significant association of IFN-gamma+874 A/T allele frequency with HBV and/or with HCV infection (chi(2) = 4.87, P = 0.18). (2) The clinical outcomes of mild chronic hepatitis (CH), moderate/severe CH and cirrhosis with HBV and/or HCV infection were associated with IFN-gamma+874 AA [chi(2) = 14.17, P = 0.03; OR = 3.09 (1.51 - 6.33), 3.85 (1.70 - 8.70), 3.14 (1.08 - 9.17)]. No significant relationships were found between IFN-gamma+874 A/T allele frequency and the clinical outcome of HBV/HCV infection (chi(2) = 6.07, P = 0.11). (3) There were no significant associations of IFN-gamma+874 genotype/allele frequency with HCV duplication (chi(2) = 2.36, P = 0.31). (4) There were no significant associations of IFN-gamma+874 genotype/allele frequency with abnormal ALT (chi(2) = 0.15, P = 0.93). These results suggested that polymorphisms in the IFN-gamma+874 had some influence on chronic HCV and/or HBV infection, and on the outcome of HCV and/or HBV infections. IFN-gamma+874 AA genotype and T allele were possible risk to chronic HBV and/or HCV infections and to the outcomes of HBV and/or HCV infection. However, IFN-gamma+874 TA genotype might serve as possible protective factors to them.

Chronic hepatitis C treatment in näive patients

Hepatitis C (HCV) is a major public health problem worldwide and it is considered that there are about 180 millions of infected people. The natural history of hepatitis C shows that, of those individuals affected by a primo-infection, 55 to 95% evolve into chronicity. The objective of treatment for chronic hepatitis C is to prevent in the long term the complications and death that this disease may cause. In a short term the most important aim is the sustained virological response (SVR), considered a virological response, normalization of the serum ALT level, histological improvement, improvement in patients’ quality of life and the risk of transmission reduction.The association Peginterferon alpha - Ribavirin (PEG IFNα-RBV), at the moment, is the standard of care of patients with chronic hepatitis C and compensated cirrhosis. Two PEG IFNα are licensed, PEG IFNα 2a and PEG IFNα 2b. Pegylation is a procedure that allows the union of polyethylene glycol moieties (PEG) to pharmacologic active proteins; in this case, IFNα. Pegylation of the IFNα 2a and 2b provoke important modifications in these proteins: slower absorption, different distribution, slower elimination, and longer half life with major exposure to the drug and lesser antigenicity. The two pegylated interferons available are dissimilar between them. The SVR in chronic hepatitis C patients who were treated with PEG IFNα-RBV in registration trials was 54 to 61%. Patients with genotypes 1 and 4 must be treated 48 weeks and those with genotypes 2 and 3, 24 weeks. In some situations patients could be treated lesser or longer time. Results obtained from the association of PEG IFNα - RBV - Amantadine in chronic hepatitis C patients are controversial.Meta-analysis comparing both PEG IFNs alpha shows a better SVR with PEG IFNα 2a. Therapies in patients with mild chronic hepatitis C have a similar SVR that those with more advanced liver disease and could be treated in this phase of the disease.

The Cirrhosis Risk Score Predicts Liver Fibrosis Progression in Patients With Initially Mild Chronic Hepatitis C

the Cirrhosis Risk Score Predicts Liver Fibrosis Progression in Patients With Initially Mild Chronic Hepatitis C

A Seven-Gene Signature (Cirrhosis Risk Score) Predicts Liver Fibrosis Progression in Patients with Initially Mild Chronic Hepatitis C†

Fibrosis progression is the main determinant of liver disease outcome in chronic hepatitis C, being influenced by environmental and host factors. Recently, a cirrhosis risk score (CRS) based on seven single-nucleotide polymorphisms was proposed as genetic predictor of cirrhosis in hepatitis C. To assess the role of CRS in predicting fibrosis progression in patients with initially no or minimal to moderate fibrosis, we investigated 271 untreated patients with chronic hepatitis C having initial liver biopsy showing METAVIR stage F0 (n = 104), F1 (n = 101), or F2 (n = 59) who had been followed up without antiviral therapies for at least 60 months (mean 108.5 +/- 71.5 months) and had a liver biopsy at the end of this observation period. Of these, 24.4% showed no histologic progression, 75.6% progressed by at least one stage, 45.0% progressed by at least two stages, and 10.3% progressed by more than two stages. The mean CRS was significantly higher (P = 0.005) in patients with fibrosis progression compared with those without progression, and this difference was particularly evident (P = 0.002) with F0 on initial biopsy. Mean CRS scores were not associated with degree of fibrosis progression. The relative risk of fibrosis progression increased with increasing CRS values. This association was significant in males but not in females and was most evident in males with F0 at initial biopsy (odds ratio 16.5, 95% confidence interval 1.6-166; P= 0.02) in the presence of high CRS. Multivariate analysis confirmed the significant association of CRS score with fibrosis progression. The predictive value of CRS was confirmed in hepatitis C virus patients admitting significant alcohol intake. Host genetics defined by CRS predict fibrosis progression in males with initially mild chronic hepatitis C and may become a useful parameter for prognostic evaluation and treatment decision.

Pathological study of liver biopsy from 156 patients clinically diagnosed with mild chronic hepatitis B based on current guideline

To study the pathological features of liver tissues from patients clinically diagnosed with mild chronic hepatitis B based on current guideline and emphasize the important significance of liver puncture and biopsy for these patients. Totally 156 patients clinically diagnosed with mild chronic hepatitis B based on current guideline received liver puncture under the real-time Doppler ultrasonographic guiding. Pathological diagnosis was made after microscopic examinations of the liver tissue specimens stained with hematoxylin-eosin (HE) and reticular fiber staining. The differences between clinical and pathological diagnosis for these patients were analyzed. Finally, 105 (67.3%) patients were pathologically diagnosed with mild chronic hepatitis B; 28 (18.0%), 3 (1.9%) and 20 (12.8%) patients were pathologically diagnosed as moderate, severe chronic hepatitis B and cirrhosis, respectively. Forty-eight (30.8%) and 39 (25.0%) patients of non-mild chronic hepatitis B were found to have G3-4 inflammation and S3-4 fibrosis, respectively. Differences in serum alanine aminotransferase, aspartate aminotransferase, total bilirubin or albumin between mild and non-mild chronic hepatitis B based on pathological diagnosis were not statistically significant (t-test, P > 0.05). Accurate pathological diagnosis is helpful to guiding an antiviral therapy.

Expression of interferon-alpha receptor in liver tissues in patients with chronic hepatitis B and its clinical significance

To detect the expression of interferon-alpha receptor (IFN-alpha R) in the liver tissues in patients with chronic hepatitis B of different pathological types, and to explore its clinical significance. Liver biopsies were conducted in 80 patients with chronic hepatitis B of different clinical types, and 60 different pathological types were screened from them. The expression of IFN-alpha R was detected by immunohistochemical technique, and its expression level was compared among different groups semi-quantitatively. The correlations between IFN-alpha R intensity and pathological types, alanine aminotransferase (ALT) level, hepatitis B surface antigen (HBsAg) concentration, hepatitis B e-antigen (HBeAg) concentration and hepatitis B virus (HBV)-DNA viral load were also analyzed by Pearson correlation test. According to pathological types, the IFN-alpha R expression intensity in liver tissues from asymptomatic carriers (12 cases) and patients with mild (20 cases), moderate (19 cases) and severe (9 cases) chronic hepatitis were 7.608+/-2.944, 8.013+/-4.722, 15.424+/-8.187 and 18.829+/-9.696, respectively. In regard to pathological grading, its expression intensity in liver tissues of G0-1 (14 cases), G1-2 (18 cases), G3 (17 cases), G4 (11 cases) was 5.096+/-0.437, 9.345+/-0.988, 13.903+/-1.409 and 23.530+/-1.965, respectively. There was a significant difference of IFN-alpha R expression intensity between groups classified by pathological types and gradings (F(1)=32.526, P(1)=0.002; F(2)=35.482, P(2)=0.001), but not by fibrosis staging (F=3.549, P=0.121). No significant correlation was found between IFN-alpha R expression intensity and HBsAg, HBeAg, HBV-DNA viral load(all P>0.05), but it was positively correlated with ALT level (r=0.546, P<0.05). The expression of IFN-alpha R in liver tissues in patients with chronic hepatitis B correlates well with the pathological grading and ALT level. The high expression of IFN-alpha R might contribute to the good response to interferon, and it could be a useful predicting factor for the therapeutic effect of interferon with chronic hepatitis B.

Pegylated and non-pegylated interferon-alfa and ribavirin for the treatment of mild chronic hepatitis C: A systematic review and meta-analysis

Traditionally, patients with chronic hepatitis C virus (HCV) infection have not received treatment until their infection reaches the moderate to severe stage. The aim of this systematic review was to assess the clinical effectiveness of pegylated (PEG) and non-pegylated interferon (IFN) alfa and ribavirin (RBV) for the treatment of adults with histologically mild HCV. We performed a sensitive search of fourteen electronic bibliographic databases for literature that met criteria defined in a research protocol. Two reviewers independently selected studies, extracted data and assessed methodological quality. Ten randomized, controlled trials (RCTs) were included. Treatment with PEG + RBV combination therapy resulted in significantly higher sustained virological response (SVR) rates than treatment with IFN + RBV combination therapy. Treatment for 48 weeks with PEG + RBV was significantly more effective than the same treatment for 24 weeks. Significantly higher SVR rates were seen with IFN + RBV compared with either IFN monotherapy or no treatment. In the meta-analysis (four IFN trials), the relative risk of not experiencing an SVR was 0.59 (95 percent CI, 0.51 - 0.69) and was statistically significant (p < .00001). SVRs were higher for patients with genotype non-1 compared with genotype 1 for both PEG + RBV and IFN + RBV treatments. Patients with histologically mild HCV can be successfully treated with both PEG and IFN combination therapy, and response rates are broadly comparable with those achieved in patients with advanced disease. Treating patients in the early milder stages of HCV is, therefore, a clinically effective option.

Hepatitis B Virus-induced hFGL2 Transcription Is Dependent on c-Ets-2 and MAPK Signal Pathway

Fibrinogen-like protein 2 (FGL2)/fibroleukin plays a pivotal role in the pathogenesis of experimental and human fulminant and chronic viral hepatitis. To define the transcription factor(s) and upstream signal transduction pathways involved in the transcription of human FGL2 (hFGL2) in response to hepatitis B (HB) virus, hepatitis B core (HBc), hepatitis B virus S protein (HBs), or hepatitis B virus X protein (HBx) protein, expression plasmids were cotransfected with an hFGL2 promoter luciferase reporter construct into Chinese hamster ovary and HepG2 cells, respectively. HBc and HBx proteins, but not HBs protein, enhanced hFGL2 transcription in both cell lines. A strong regulatory region from -712 to -568 (relative to the transcriptional starting site) was shown to be responsible for hFGL2 gene transcription in response to both HBc and HBx proteins. c-Ets-2 was shown to be translocated to the nucleus in association with hFGL2 expression in response to both HBc and HBx proteins. Short hairpin RNA (shRNA) interference of c-Ets-2 expression inhibited hFGL2 gene transcription by 64.8 and 60.0% in response to HBc and HBx, respectively. c-Ets-2 protein was highly expressed in peripheral blood mononuclear cells from patients with severe chronic hepatitis B (CHB) in contrast to patients with mild CHB. Increased phosphorylation of ERK and JNK was detected in peripheral blood mononuclear cells from patients with severe CHB. ERK inhibitor PD098059 or ERK shRNA abolished the nuclear c-Ets-2 DNA binding activity and hFGL2 induction in response to HBc, whereas JNK inhibitor SP600125 or JNK shRNA abolished the nuclear c-Ets-2 DNA binding activity and hFGL2 induction in response to HBx. In conclusion, HBc and HBx proteins enhance transcription of hFGL2 through c-Ets-2 dependent on MAPK signal pathways.

Is management with lamivudine always the appropriate choice for HBV patients with onco-hematologic diseases?

Dear Editor, We read with interest the article by Yi-Fu H. et al. [1] about the effectiveness of Lamivudine (LAM) prophylaxis in preventing hepatitis B viral (HBV) reactivation in Rituximab containing regimens (so called immunochemotheraphy, ICT) for lymphoma and would like to make a contribution to this emerging topic. All patients diagnosed with Non-Hodgkin Lymphoma (NHL) from January 2005 to March 2008, at our Institution, were screened for HBV serology: HBsAg, anti-HBs, anti-HBc, HBeAg, anti-HBe. Patients were also tested for HCV antibodies (HIV-positive patients were not included): 18 out of 159 patients (11.3%) had serological signs of HBV exposure. 12 out of 159 (8.1%) patients were HCV-infected. Seven out of 18 HBV carriers were coinfected with HCV (38.8%). In 11 out of 18 patients (61%), HBsAg were negative [2], anti-HBc (nine patients), anti-HBs (one patient, no history of previous vaccination), anti-HBc/anti-HBe/anti-HBs (one patient) being the only positive markers of previous HBV exposure. Three patients were known to be affected by mild HBV chronic active hepatitis at the time of lymphoma diagnosis and were treated with LAM to contain the disease process before and after ICT. The remaining four inactive HBsAg carriers and the 11 HBsAg-negative/antiHBc-positive patients were started on LAM as a preemptive treatment to prevent possible disease reactivation [3]. Patients began treatment with LAM 100 mg/day po on average 3–4 weeks before embarking on chemotherapy, after signing informed consent. All 159 patients were given R-CHOP or R-CHOP-like regimens [4]. LAM treatment was extended to 18 months after that the new indications from the dedicated commission of the Italian Study of the Liver became widely available in 2007 [3]. During and after ICT discontinuation, patients were tested every 2 months for HBsAg, quantitative-HBV-DNA, ALT, and AST. Median follow-up time was 7 months (range 3–43). Five of the seven HBsAg-positive patients (71.4%) became HBV-DNA positive during follow-up at 25, 18, 18, 10, and 7 months after commencing LAM. In two patients, emergence of HBV-DNA positivity was associated with an increase of serum transaminases (up to five times the upper normal limit). In these five patients, AdefovirDipivoxyl, 10 mg/day po, was combined with LAM, resulting in a disappearance of HBV-DNA and regression of the biochemical signs of hepatitis. None of these patients had to discontinue ICT because of HBV reactivation. No liver-related deaths occurred. None of the HBcAbpositive, anti-HBs-positive/HBsAg-negative patients (potential silent carriers) developed HBV reactivation during the period of observation. No side effect related either to LAM or ADV was registered. Four out of seven of these patients are now undergoing new treatments because of lymphoma progression. The prevalence of HBV infection is high among patients diagnosed with NHL as compared to less than 2% of the Italian adult population [5]. Reactivation of HBV infection can present a serious threat to these patients and to the Ann Hematol (2009) 88:283–284 DOI 10.1007/s00277-008-0609-2

Fatal Autoimmune Hepatitis Induced by Concurrent Loss of Naturally Arising Regulatory T Cells and PD-1-Mediated Signaling

Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH. To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments. In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. In contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma. NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.

Assessment of Silent Liver Fibrosis in Hemochromatosis C282Y Homozygotes With Normal Transaminase Levels

Population screening studies for hemochromatosis have demonstrated an increase in liver disease in C282Y homozygotes, but many participants have no evidence of liver dysfunction. Previous studies have suggested that liver fibrosis in hemochromatosis might be silent. The objective of this study was to assess the degree of liver injury in referred C282Y homozygotes who underwent elective liver biopsy and had serum AST and ALT levels < 40 IU/L. All C282Y homozygotes who underwent liver biopsy with normal AST and ALT levels were included in this study. There were 35 men and 16 women in the study with a mean age of 51 years (range, 16-89). The mean serum ferritin level was 637 microg/L (range, 18-2062), and mean liver iron concentration was 131 micromol/g (range, 11-386). There were 42 patients with no fibrosis, 6 patients with fibrosis, and 3 patients with cirrhosis. Silent liver fibrosis with normal transaminase levels is seen in 18% of referred C282Y homozygotes. Studies that have reported on biochemical liver dysfunction in hemochromatosis might have underestimated the prevalence of liver injury from iron overload.

Chronic hepatitis C genotype 2 or 3 short treatment

Dalgard et al.1 reported interesting data on 14 versus 24 weeks of combination therapy in patients with hepatitis C virus (HCV) genotype 2 or 3, and they concluded that it is rational to treat those patients with rapid virological response (RVR) for only 14 weeks. Adequate treatment duration is generally considered decisive in order to improve adherence and reduce side effects. At present, the strategy involves adapting therapy to each individualized case instead of adapting the patient to an established regimen.2, 3 Young, white, nonobese patients with low viremia, infected by genotype 2 or 3 HCV, with low fibrosis and RVR could receive shorter treatment.2, 3 However, the point regarding duration may be elusive and, in spite of some studies,4, 5 definite conclusions are still lacking. The current experience of our group is in agreement with the results by Dalgard et al.1 The well-documented case of a patient adds further support to the value of the short regimen in patients with genotype 2 or 3 and RVR. A 34-year-old Spanish woman, with a body mass index of 21 kg/m2, moderate alanine aminotransferase (ALT) serum levels (64 IU/L), HCV-3a genotype infection, HCV RNA 5.7 × 105 IU/mL, and mild chronic hepatitis on biopsy (grade 2, stage 1–2), was initiated treatment with peginterferon α-2a (180 μg/weekly) plus ribavirin (800 mg/daily) on August 29, 2001. At week 4, the patient attained an RVR with normal ALT levels (13 IU/L). The tolerance was excellent but after receiving combination therapy during 10 weeks, she presented with fever and productive cough; chest radiography led to a diagnosis of pulmonary tuberculosis, documented by bacilli culture and sputum smears. Premature withdrawal (November 6, 2001) from antiviral treatment was required. Then, tuberculostatic therapy was started and maintained for 36 weeks with good tolerance. During this time, serum ALT levels were persistently normal and HCV RNA remained negative in three determinations carried out at weeks 12, 24, and 48. A second liver biopsy obtained at year 4 after antiviral withdrawal demonstrated no inflammation (A0) or fibrosis (F0). It can be concluded that: (1) Fewer side effects and their more limited duration are in favor of the short treatment regimen in patients with genotype 2 or 3 and RVR; (2) Short therapy is able to eradicate HCV and cure chronic hepatitis C in these patients; (3) Optimal treatment duration needs to be defined for each individualized patient; and (4) Further studies including customized management and therapeutic regimens based on virological characteristics (genotype and viremia), demographic aspects, liver disease severity, and individual genomic-marker analysis are warranted. Whether all points of this strategy have similar relevance with imminent new therapies remains to be investigated. Ricardo Moreno-Otero M.D.*, María Trapero M.D.*, José A. Moreno-Monteagudo M.D.*, * Digestive Diseases Service and CIBEREHD, University Hospital of La Princesa, Autonomous University of Madrid, Madrid, Spain.

Onset of bronchiolitis obliterans organizing pneumonia in a liver transplant recipient under peg-interferon and ribavirin treatment

A 63-year-old man underwent orthotopic liver transplantation (OLT) on January 26, 2005 for hepatocellular carcinoma (HCC) on HCV related cirrhosis (HCV genotype 2a/2c). The patient was HBsAb, HBcAb and HBeAb positive (HBsAb = 316 mU/ml) and anti-cytomegalovirus (CMV) negative. HBV DNA (bDNA) in the serum was negative, HCV viremia (PCR) was 0.86 MEq/ml 1 month before OLT. The donor was HBcAb and anti-CMV positive. The autoimmunitary pattern was completely negative. Therapy at the discharge after transplantation was based on steroid, tacrolimus, valganciclovir and lamivudine. Steroid and lamivudine therapy were continued for 5 and 3 months respectively. His history was also significant for insulin dependent diabetes, arisen under immunosuppressive therapy. One month after OLT, the patient was submitted to liver biopsy because of an increase in transaminases (AST = 97 U/l, ALT = 159 U/l, normal range 0–40 U/l): no signs of rejection were observed but only a mild periportal necrosis with inflammation. HCV antigen, evaluated with immunohistochemical reaction, was present in more than 50% of hepatocytes. A further increase in transaminases occurred 3 months later (AST = 66 U/l, ALT = 137 U/l), thus the patient underwent a second liver biopsy: this time histological analysis demonstrated clearly a mild active chronic hepatitis HCV related (Knodell score 8, Ishak 14) and no evidence of rejection again. HCV RNA level was 4.35 mEq/ml. Therapy with pegylated interferon alpha 2a and ribavirin (Pegasys 180 mcg once a week plus ribavirin 600 mg/die) was started in July 2005. Liver enzymes rapidly normalized and HCV RNA became negative within a month. Eight weeks after starting this treatment, the patient complained of very intense asthenia and fever; physical examination revealed wheezing and crackles in left pulmonary base, chest x-ray demonstrated a suspicious inflammatory infiltrate in left inferior lobe. Treatment with oral ciprofloxacin and IM piperacillin + tazobactam, was commenced, but 3 days later, he was admitted to our ward for fever persistence. Peg-INF and RIBA were stopped when the patient was hospitalized. On admission he looked pale, lightly dyspnoic; he complained of severe asthenia. No other significative finding was present at physical examination beside the pulmonary one. Temperature was 39 C (102.2 F). Laboratory tests showed a white blood cell count of 6.72 9 10/ll (range 4.00–9.00 9 10/ll), 85% neutrophils, hemoglobin 7.5 g/ dl (range 12–15), ESR 71 mm/h (range 0–36), C-reactive protein 3.96 mg/dl (\0.8), LDH 567 U/l (range 230–460), AST 61 U/l, ALT 34 U/l, c-GT 247 U/l (range 0–50). Arterial blood gas analysis (room air) revealed pH = 7.46, PaCO2 = 34.6 mmHg, PaO2 = 112 mmHg. Tacrolimus serum level was 9.0 ng/ml. The anemia, ascribed to bone marrow depression and emolysis, induced by antiviral therapy, was treated with 2 U packed red blood cells. Because of the presence of various immunodepressant conditions (tacrolimus and interferon treatment, diabetes) an infective cause appeared to be the most likely explanation of fever and pulmonary infiltrates. Serologic tests for bacterial, viral and fungal agents (Legionella, Chlamydia, Mycoplasma pneumoniae, HIV, Parvovirus, EBV, Herpes SimplexVirus, Leishmania, Aspergillus, Cryptococcus) were negative. Only CMV antigenemia pp65 was positive (4 cells/ll). Quantitative C. Crespi (&) S. Gualandi F. Piscaglia L. Bolondi Dipartimento Malattie dell’Apparato Digerente e Medicina Interna, UO Medicina Bolondi, Azienda Ospedaliera Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy e-mail: cristina.crespi@aosp.bo.it

Host-Range and Pathogenicity of Hepatitis B Viruses

Hepatitis B viruses are small enveloped DNA viruses referred to as Hepadnaviridae that cause transient or persistent (chronic) infections of the liver. This family is divided into two genera, orthohepadnavirus and avihepadnavirus, which infect mammals or birds as natural hosts, respectively. They possess a narrow host range determined by the initial steps of viral attachment and entry. Hepatitis B virus is the focus of biomedical research owing to its medical significance. Approximately 2 billion people have serological evidence of hepatitis B, and of these approximately 350 million people have chronic infections (World Health Organisation, Fact Sheet WHO/204, October 2000). Depending on viral and host factors, the outcomes of infection with hepatitis B virus vary between acute hepatitis, mild or severe chronic hepatitis or cirrhosis. Chronic infections are associated with an increased risk for the development of hepatocellular carcinoma.

Natural History and Clinical Impact of Cryoglobulins in Chronic Hepatitis C: 10-Year Prospective Study of 343 Patients

Serum cryoglobulins (CGs) are present in patients with chronic hepatitis C virus (HCV) infection, but their long-term clinical importance has not been established. We assessed the development rates, morbidity, and influence on the evolutionary course of hepatitis C of CG. A cohort of 343 HCV-RNA seropositive outpatients (173 men; age, 58 y; 82 with cirrhosis; 61 treated with interferon) with persistently increased aminotransferase levels and histologically defined liver disease was investigated. Patients initially were investigated for the presence, amount, and type of CG and prospectively followed up with clinical and laboratory examinations every 6 months. At enrollment, CGs were found in 163 (47%) patients at a mean level of 173 +/- 142 mg/L; 80% were type III, and associated to female sex (61% vs 40%, P = .0002) and cirrhosis (29% vs 19%, P = .04). Over the course of 17-130 months (median, 116 mo), de novo CG developed in 25 patients (2.3% per year), including 5 with cryoglobulinemic syndrome (.3% per year). The 10-year rates of progression to cirrhosis and of liver and extrahepatic complications were similar in CG (+) and CG (-) patients (32% vs 34%; 23% vs 16%; 5% vs 3%). The 10-year survival rates were lower for cirrhotic than for noncirrhotic patients (57% vs 91%, P < .00001), independently of CGs. CGs are common in patients with chronic HCV infection, mainly are type III, and do not influence the clinical course of hepatitis C during the first decades, except for the few rare cases of cryoglobulinemic syndrome.

Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation

To assess the clinical effectiveness and cost-effectiveness of pegylated interferon alpha (PEG) and non-pegylated interferon alpha (IFN) and ribavirin (RBV) for the treatment of adults with histologically mild chronic hepatitis C (HCV) infection. Electronic bibliographic databases were searched up to July 2005. A systematic review and an economic evaluation were carried out. A Markov state transition model was developed to estimate the cost-effectiveness of treatment strategies for adults with mild chronic HCV. Among the included studies, eight randomised controlled trials (RCTs) of antiviral treatment in mild HCV were identified and included. In general these RCTs were of good quality. The results suggested that effectiveness, particularly with respect to sustained virological response was similar in patients with mild disease to the results obtained in patients with moderate/severe disease. This finding was supported by RCTs reporting the results for mild HCV sub-groups. The authors' cost-effectiveness analysis showed that early treatment compared with watchful waiting is associated with quality-adjusted life-year (QALY) gains but with increased treatment costs. The base-case incremental costs per QALY for 48 weeks of treatment are: watchful waiting with IFN + RBV versus best supportive care = pound 3097-6585; early treatment with IFN + RBV versus watchful waiting with IFN + RBV = pound 5043-8092; watchful waiting with PEG 2a + RBV versus best supportive care = pound 3052; early treatment with PEG 2a + RBV versus watchful waiting with PEG 2a + RBV = pound 5900; watchful waiting with PEG 2b + RBV versus best supportive care = pound 2534; and early treatment with PEG 2b + RBV versus watchful waiting with PEG 2b + RBV = pound 5774. These results were consistent with previous assessments of cost-effectiveness. This systematic review and economic evaluation show that patients with histologically mild HCV can be successfully treated with both pegylated and non-pegylated interferon alpha. Early treatment and watchful waiting strategies are associated with acceptable cost-per-QALY estimates. Research needs to be directed towards newer, potentially more effective interventions, particularly those that improve treatment response in patients with genotype 1, with minimal adverse effects. Further research is required into the natural history of HCV to estimate better the rate of liver disease progression, and also into the effectiveness of non-invasive biochemical markers of liver disease, as an alternative to liver biopsy.

A health economic model to assess the cost‐effectiveness of PEG IFN α‐2a and ribavirin in patients with mild chronic hepatitis C

According to the current guidelines, it is advised not to treat patients with mild chronic hepatitis C. However, discussions as to giving immediately a treatment (direct treatment) to these patients have started and the incremental cost-effectiveness ratio (ICER) of such strategy is still unknown. The aim of this study was to estimate, in the health care payer perspective, the ICER of a direct treatment of patients with mild chronic hepatitis C in comparison with the strategy of monitoring these patients and treat them when the disease will progress to the state of moderate chronic hepatitis. The treatment assessed was the current standard treatment composed of pegylated interferon alpha-2a and ribavirin. At the beginning of the study, patients were aged 45. Long-term economic and clinical outcomes over a 30-year period were predicted using a Markov simulation model. Data were obtained from published literature. Monte Carlo simulations were used to determine 95% confidence intervals of results. The ICER of a direct treatment with PEG IFN alpha-2a and ribavirin is 23,046 euro/QALY (CI 95% 3,882 euro-42,392 euro) for genotypes 1-4-5-6 and 4,631 euro/QALY (CI 95% 797 euro-7,881 euro) for genotypes 2-3. Sensitivity analysis shows that it is only in extreme circumstances related to the utilities that the ICER for genotypes 1-4-5-6 is unacceptably high for the society (>50,000 euro). Even though a direct treatment is more expensive, it gives the advantage of curing greater number of patients and of increasing quality-adjusted life-years (QALYs), implying that such strategy is generally cost-effective at a threshold of 50,000 euro/QALY.

Utilidad de los parámetros analíticos en el diagnóstico de las enfermedades hepáticas

Liver function tests include biochemical parameters (AST, ALT, GGT or Alkaline phosphatase), bilirubin and albumin levels and coagulation tests as prothrombin activity. These tests are commonly used in the routine screening even in symptomatic as in asymptomatic patients, and the right evaluation of the results is of vital importance. Cytolytic elevation in serum aminotransferases: In mild chronic elevation pharmacological toxicity, viral hepatitis, alcoholic and non-alcoholic fatty liver disease and hemochromatosis, should be excluded. Cholestatic elevation os serum enzymes: The first option should be to establish the origin of the alkaline phosphatase elevation, with the evaluation of the GGT levels to confirm the hepatic origin. The next step should be to distinguish the presence of an extrahepatic (biliary obstruction) or intrahepatic (PBC, PSC, drugs, etc) cholestasis, in these cases the most important test should be the abdominal ultrasound, in order to evaluate the biliary system. Hyperbilirubinemia: Non conjugated hyperbilirubinemia (hemolysis, ineffective erythropoiesis, Gilbert or Criggler-Najjar syndromes) and conjugated hyperbilirubinemia, an unusual situation in which Rotor and Dubin-Johnson Syndromes should be considered. The evaluation of albumin and prothrombin levels evaluates the hepatic function per se, allowing to differentiate between acute and chronic diseases. At present, there are not prospective studies to evaluate the efficacy of the liver function tests. To carry out a complete medical history, an appropriate physical examination and the appropriate application of non-invasive diagnostic tests (serology, iron levels, autoimmunity or abdominal ultrasound) allow to perform a right diagnosis in most patients, making more complex tests, including liver biopsy, secondary.

Fallo hepático fulminante por un linfoma no hodgkiniano de estirpe T asociado al virus de la hepatitis C. Caso clínico

Hematological malignancies can affect the liver, without producing severe hepatic involvement. We report the case of a 57-year-old man with hepatitis C virus infection and mild chronic hepatitis without antiviral treatment, who developed an aggressive T-cell non-Hodgkin's lymphoma confirmed by histological studies including liver, lymph nodes and bone marrow. The patient developed massive hepatic infiltration and acute liver failure. Rescue chemotherapy was administered but the patient died soon after with severe lactic acidosis. The immunopathological features of this association and the few reports of cases presenting with acute liver failure are reviewed.

Glycogen Pseudoground Glass Change in Hepatocytes

Ground glass cytoplasmic change in hepatocytes is typically associated with chronic hepatitis B infection. We report 12 cases of glycogen pseudoground glass change that closely mimics hepatitis B inclusions. Nine individuals were immunosuppressed secondary to liver or kidney transplant (N=3), bone marrow transplant (N=2), HIV infection (N=2), kidney dialysis (N=1), or chronic inflammatory bowel disease (N=1). Medication history was available in 10 individuals and all were on multiple medications (range 2 to 33). Histologically, the pseudoground glass change was identical to the ground glass change seen in chronic hepatitis B infection, with distinct, circumscribed, gray-glassy inclusions surrounded by a rim of cytoplasm. The background livers showed mild or no inflammation and mild or no fibrosis. All cases were negative for chronic hepatitis B infection. The pseudoground glass change was PAS positive and diastase sensitive. Electron microscopy of the inclusions showed glycogen in 3/3 cases. No evidence for viral particles or significant endoplasmic reticulum proliferation was seen. Three cases had follow-up biopsies (1, 1, and 36 mo), and the pseudoground glass was persistent in 2 cases and showed partial resolution in 1 case (1 mo biopsy interval). We conclude that glycogen pseudoground glass change is typically seen in immunosuppressed individuals on numerous medications. The changes are generally seen in the background of mild chronic hepatitis with mild or no fibrosis. Glycogen pseudoground glass change can resolve, but may also persist for years.