Flares In Chronic Hepatitis Research Articles

FRI-391 Relapse incidence and severe flares in chronic hepatitis B patients with lymphoma post rituximab-based chemotherapy versus HBeAg-negative hepatitis B patients without cancer after nucleos (t)ide analogue cessation

FRI-391 Relapse incidence and severe flares in chronic hepatitis B patients with lymphoma post rituximab-based chemotherapy versus HBeAg-negative hepatitis B patients without cancer after nucleos (t)ide analogue cessation

The prevalence and risk factors of hepatitis B flares in chronic hepatitis B patients receiving glucocorticoid pulse therapy.

Background The frequency and risks of hepatitis B reactivation in patients receiving glucocorticoid pulse therapy has not been reported. Objective The aim of our study was to investigate the possibility of glucocorticoid pulse therapy related hepatitis B flare. Setting A Taiwanese tertiary hospital. Methods Chronic hepatitis B patients underwent glucocorticoid pulse therapy were retrospectively collected. The prevalence of hepatitis B flare was counted, and the statistic analysis with logistic regression was adapted to assess the associated risk factors. Main outcome measure The prevalence and associated risk factors of the individuals with hepatitis B flare after glucocorticoid pulse therapy were collected and analyzed. Results A total of 112 patients were identified. Forty patients had received prophylactic antiviral therapy and none of them developed hepatitis B flare. Among the 72 patients who had not received antiviral prophylaxis, 11 of them (15.3%) experienced hepatitis B flares. Those individuals with hepatitis B flares, comparing to those without, were younger (37.4±13.3 vs. 46.0±11.1, p=0.038), had higher ratio of HBeAg positivity (50 vs. 15.9%, p=0.017), higher percentage of high hepatitis B viral load (81.8 vs. 8.3%, p=0.002), higher maintenance glucocorticoid dose (prednisone or equivalent 22.7±14.9 vs. 10.7±12.4mg, p=0.003) and higher ratio of cyclophosphamide use (27.3 vs. 1.6%, p=0.010). After multivariate analysis, only higher dose of maintenance glucocorticoid was related to hepatitis B flare (odds ratio, 1.08; 95% CI, 1.01-1.16). Conclusion A higher maintenance glucocorticoid dosage is associated with the risk of hepatitis B flare after glucocorticoid pulse therapy. No hepatitis B flare occurred in patients receiving prophylactic antiviral therapy before glucocorticoid pulse therapy.

Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.

Therapeutic duration of nucleos(t)ide analogues for chronic hepatitis B (CHB) is not indefinite in many parts of the world. Viral reactivation is common off therapy, but the risk of subsequent clinical outcome remains unclear and unpredictable. We aimed to quantify the incidence of and explore the predictors for clinical flare following virological relapse in CHB patients who discontinue entecavir therapy. This multicenter cohort study prospectively monitored 133 CHB patients who were HBeAg-negative and viral DNA-undetectable when discontinuing entecavir after at least 3years on therapy. Following virological relapse (viral DNA >2,000IU/mL) that occurred in 92 patients, the incidences of subsequent clinical flare and persistent (unremittent for 3months) or severe hepatitis (with jaundice or coagulopathy) were determined, and risk factors were explored. Patients did not resume antiviral therapy until occurrence of persistent or severe hepatitis. The cumulative incidence of clinical hepatitis 2years after virological relapse was 61.0% (95% confidence interval [CI], 49.9-72.3%) and that of persistent or severe hepatitis was 53.0% (95% CI, 40.9-66.2%). Serum viral load at the virological relapse was associated with both clinical hepatitis (adjusted hazard ratio [HR], 1.31 per log IU/mL; 95% CI, 1.07-1.60) and persistent or severe hepatitis (adjusted HR, 1.63 per log IU/mL; 95% CI, 1.27-2.10), after adjustment for serum aminotransferase and alfa-fetoprotein levels in the multivariate analysis. Viral DNA >100000IU/mL predicted a nearly inevitable occurrence of clinical flare (P<0.0001). A high viral load at the virological relapse predicts subsequent clinical hepatitis in CHB patients who discontinue entecavir.

A Spontaneous Acute Flare of Chronic Hepatitis B Without an Obvious Cause

A Spontaneous Acute Flare of Chronic Hepatitis B Without an Obvious Cause

Remission of splenic marginal zone lymphoma in a patient treated for hepatitis B: a case of HBV-associated lymphoma

Splenomegaly is a common finding in chronic hepatitis B infection. We present the case of a man with an acute flare of chronic hepatitis B infection, where splenomegaly in absence of portal hypertension led to the diagnosis of splenic marginal zone lymphoma (SMZL) with bone marrow involvement. Adequate suppression of the hepatitis B virus (HBV) viral load with tenofovir resulted in complete remission of the lymphoma.

Hepatobiliary Quiz—9 (2014)

1.Regarding acute hepatitic illnesses in patients with chronic hepatitis B (CHB) infection the following are TRUE:1.Most common cause is flare of hepatitis B2.Flare of hepatitis B is more common in HBeAg negative individuals3.Flares of hepatitis B can be due to activation of immune system or due to reactivation of hepatitis B virus4.Reactivation of hepatitis B virus invariably occurs in the setting of immunosupression5.Reactivation of hepatitis B virus does not occur in HBsAg negative patients2.Regarding differentiation of acute hepatitis B infection from flare of chronic hepatitis B the following are TRUE EXCEPT:1.Presence of serum IgM anti-HBc is pathognomonic for acute hepatitis B infection2.In acute hepatitis B infection the 19s subtype of IgM anti-HBc is more common3.IgG anti-HBc can be seen in both acute hepatitis B as well as reactivation of chronic hepatitis B infection4.Hepatitis B DNA levels are higher in acute hepatitis B infection5.HBsAg and HBeAg titres are lower in acute hepatitis B infection3.Regarding pathogenesis and clinical features of Wilson disease the following are TRUE:1.Wilson disease occurs due to mutations in ATP7A gene2.Wilson disease is inherited in an autosomal recessive pattern3.Wilson disease has a definite phenotype–genotype correlation4.Liver disease manifests at earlier age than neurological disease5.Most patients with neurological presentation of Wilson disease will have underlying liver disease4.Regarding the diagnosis of Wilson disease the following are TRUE:1.Kayser–Fleischer ring is almost universally present in patients with neurological Wilson disease2.Total serum copper is reduced in Wilson disease3.Low ceruloplasmin levels are specific for Wilson disease4.d-Penicillamine challenge test is useful to diagnose Wilson disease in adults and asymptomatic siblings of affected patients5.Testing for H1069Q mutation is useful to establish the diagnosis in Indian patients5.Regarding treatment of Wilson disease the following are TRUE EXCEPT:1.Zinc acts by increasing urinary excretion of copper2.d-Penicillamine may cause initial worsening of neurological symptoms3.Trientine is contraindicated in patients intolerant to d-Penicillamine4.Ammonium tetrathiomolybdate may be useful for patients whose neurological disease worsens with other chelators5.Development of anemia or leukopenia during chelation therapy may be due to copper deficiency6.Regarding the pathophysiology of neonatal hemochromatosis the following are TRUE:1.Neonatal hemochromatosis is a hereditary disorder2.Gestational alloimmune liver disease (GALD) is the probable cause of neonatal hemochromatosis3.GALD is an IgM mediated disease4.Complement mediated hepatocyte injury via the classical pathway is the hallmark of GALD5.Histopathological changes are panlobular, and typically spare the portal tracts7.Regarding presentation and diagnosis of neonatal hemochromatosis the following are TRUE:1.Most cases will present after few weeks of birth with liver failure2.Hepatic transaminase levels are very high3.α-fetoprotein levels are very high4.Serum ferritin is very high and transferrin levels are low5.Presence of extrahepatic siderosis is helpful in making the diagnosis8.Regarding treatment and prevention of neonatal hemochromatosis the following are TRUE:1.Iron chelators are useful2.Plasma exchange and intravenous immunoglobulin (IVIg) are therapy of choice3.Liver injury in neonatal hemochromatosis is irreversible with therapy4.Liver transplantation has excellent success rates5.Women with prior affected babies should receive IVIg prophylaxis in subsequent pregnancies9.Regarding donor selection for deceased donor liver transplantation the following are TRUE EXCEPT:1.The ideal donor is less than 40 years of age and has trauma as cause of death2.Ideal donor includes donation after cardiac death3.Ideally the serum sodium of the donor should be below 150 mEq/L4.Exogenous hormone therapy like thyroid hormones and corticosteroids given prior to organ procurement in brain dead donors improves transplantation outcomes5.The Model for End-stage Liver Disease (MELD) score is the best predictor of post-transplant outcomes10.Regarding extended criteria donors for deceased liver transplantation the following are TRUE:1.Cold ischemia time is an important determinant of post-transplant outcomes in grafts from extended criteria donors2.High levels of hepatic transaminases in the donor are a contraindication for liver donation3.The risk of transmission of malignancy via hepatic graft is about 1%4.Organs from donors with previously treated low grade malignancies may be considered for transplantation5.Outcomes from liver grafts from non-heart beating donors are invariably poor

Hepatic flares in chronic hepatitis C: spontaneous exacerbation vs hepatotropic viruses superinfection.

The hepatitis C virus (HCV) causes an acute infection that is frequently asymptomatic, but a spontaneous eradication of HCV infection occurs only in one-third of patients. The remaining two-thirds develop a chronic infection that, in most cases, shows an indolent course and a slow progression to the more advanced stages of the illness. Nearly a quarter of cases with chronic hepatitis C (CHC) develop liver cirrhosis with or without hepatocellular carcinoma. The indolent course of the illness may be troubled by the occurrence of a hepatic flare, i.e., a spontaneous acute exacerbation of CHC due to changes in the immune response, immunosuppression and subsequent restoration, and is characterized by an increase in serum aminotransferase values, a frequent deterioration in liver fibrosis and necroinflammation but also a high frequency of sustained viral response to pegylated interferon plus ribavirin treatment. A substantial increase in serum aminotransferase values during the clinical course of CHC may also be a consequence of a superinfection by other hepatotropic viruses, namely hepatitis B virus (HBV), HBV plus hepatitis D virus, hepatitis E virus, cytomegalovirus, particularly in geographical areas with high endemicity levels. The etiology of a hepatic flare in patients with CHC should always be defined to optimize follow-up procedures and clinical and therapeutic decisions.

Dynamic change of hepatitis B surface antigen expression in chronic hepatitis B patients during the natural recovery course and the short-term antivirus treatment

To investigate the dynamic quantitative changes in expression of hepatitis B virus (HBV) surface antigen (HBsAg) that occurs during the natural recovery course and the short-term antivirus treatment period of patients suffering from flares in chronic hepatitis B (CHB). CHB patients presenting for treatment of flare-ups were randomly assigned to receive treatment with Entecavir antiviral (group A, n = 39) or to naturally resolve the acute condition (group B, n = 22). All patients MELD scores were calculated and HBsAg levels and HBV DNA loads were measured upon admission (baseline), at worst-condition stage, and end of treatment/flare-up (discharge). Pairwise comparisons of intergroup differences were made to evaluate the change in the three disease parameters over time in response to the management approach. The levels of HBsAg were not significantly different between the two groups at baseline, worst-condition stage and discharge (group A: (3.68+/-0.45), (3.84+/-0.19) and (3.69+/-0.58) log10 cut-off index (COI) respectively; group B: (3.59+/-0.54), (3.47+/-0.76) and (3.43+/-0.68) log10 COI respectively; all P more than 0.05). However, the HBV DNA loads were significantly lower in group A than in group B at the worst-condition stage and at discharge (all P less than 0.05). In group A, the MELD scores were significantly higher at baseline and at worst-condition stage than at discharge (all P = 0.000), but the difference between baseline and worst-condition stage was not significant. Also in group A, the HBV DNA load showed a gradually decreasing trend over time (baseline more than worst-condition stage more than discharge, all P less than 0.05). No significant differences were observed over time in the HBsAg levels of group A. In group B, the MELD scores were significantly higher at baseline and at worst-condition stage than at discharge (all P = 0.000), but the difference between baseline and worst-condition stage was not significant (P = 0.619). Also in group B, the HBV DNA loads were significantly higher at baseline and worst-condition stage than at discharge (P = 0.000 and P = 0.003 respectively), but the difference between baseline and worst-condition stage was not significant. Finally, no significant differences were observed over time in the HBsAg levels of group B. Natural recovery from an acute flare-up of CHB is not accompanied by a change in HBsAg levels. In addition, short-term antiviral treatment to resolve the flare-up has no influence on HBsAg level.

Frequency and clinical outcomes of flares related to nucleos(t)ide analogue therapy in patients with chronic hepatitis B

Flares in chronic hepatitis B are often detrimental but sometimes lead to sustained immune control and disease remission. The aim of this study was to estimate the frequency of hepatitis flares which occur during and/or after cessation of nucleos(t)ide analogue (NA) therapy, and to assess their outcomes. In a single centre cohort study we investigated 227 patients who received a total of 351 NA treatment courses. NA therapy was discontinued after 149 treatment courses. In total, 27 flares were observed during 9779 on-treatment patient-months. The frequency was estimated as 3.2 per 100 person-years (95% CI 2.2-4.7). Lamivudine (LAM)-treated patients demonstrated the highest frequency (4.9/100 person-years, 95% CI 3.2-7.4). Twenty (74%) of 27 on-therapy flares were associated with development of genotypic resistance, which all occurred during LAM therapy. NA withdrawal flares occurred after a median post-treatment follow-up of 3.5 months in 17 (11%) of 149 treatment discontinuations. No flares were observed in patients who switched to another antiviral agent (n = 51). None of the on-therapy and withdrawal flares related to NA therapy were associated with sustained disease remission, and seven flares resulted in decompensated liver disease. In this study, flares related to NA therapy never led to immune control and sustained disease remission, and sometimes resulted in decompensated liver disease.

Zwei Autopsiefälle mit systemischer Amyloidose – Fall 11/2010

A 37-year old patient was admitted with upper abdominal pain, vomiting and diarrhea. A 38-year-old patient was admitted for liver failure. Case 1 was diagnosed with an AL amyloidosis due to deposition of the immunoglobulin light chain kappa in all tissues analyzed. In the bone marrow plasma cells were increased to 20-30%. Case 2 suffered from AA amlyoidosis secondary to familial mediterranean fever and underwent dialysis treatment for years. He was positive for hepatitis B and C. Patient 1 developed refractory nephrotic syndrome and low blood pressure. During hemodialysis circulatory failure occured and she died during resuscitation. In patient 2 a flare of chronic hepatitis B was found and treated with antiviral therapy. He was referred to ICU for rectal bleeding and developed pulmonary arrest. After resuscitation he died because of lactate acidosis and refractory circulatory failure. Both cases were subjected to autopsy. The vast majority (90%) of amyloidoses are due to acquired AA or AL amyloidosis. Prognosis remains poor, in particular when cardiac and vascular involvement occurs.

A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B

The pathogenesis of hepatic flares (HF) in patients chronically infected with hepatitis B virus (HBV) is controversial. Therefore, we studied the kinetics of innate and adaptive immune activation during HF in chronic hepatitis B. Soluble (IFN-alpha, IL-1beta, TNF-alpha, IL-6, IL-8, IL-10, CCL-2, CCL-3, CXCL-9, CXCL-10) and cellular (HBV-specific T cells, NK, Treg) immunological parameters were measured longitudinally (10 month-4 week intervals) in patients (n=5) who developed HF after therapy withdrawal and cross-sectionally in chronic (n=29) and acute hepatitis B patients (n=5). Hepatic expression of different chemokines was studied by co-incubating cytokines (IFN-alpha, IFN-gamma, TNF-alpha) and activated T, NK and monocytes with hepatocytes and hepatocyte-like cells. A progressive increase of HBV replication precedes HF but occurs without detection of innate immune activation, with the exception of increased serum CXCL-8. Despite the absence of increased circulatory HBV-specific T or activated NK cells, HF were temporally associated with high serum levels of IFN-gamma inducible chemokines CXCL-9 and CXCL-10 (but not CCL-2 or CCL-3). CXCL-9 and CXCL-10 displayed different in vitro requirements for activation and are differentially produced in liver injury present in acute or chronic patients. CXCL-9 and CXCL-10 play a major role in the development of HF. Their differential expression in acute versus chronic patients suggests the presence of different mechanisms that govern liver injury during acute and chronic hepatitis B.

A Novel Immunocompetent Rat Model of HCV Infection and Hepatitis

Hepatitis C virus (HCV) infects millions of people worldwide. Therapy is limited, and treatment does not produce a sustained response in the majority of patients. Development of new agents has been hampered by the lack of a convenient animal model. The aim of this study was to determine whether an immunocompetent rat, tolerized and transplanted with a human hepatoma cell line (Huh 7 cells), could be used to sustain an HCV infection. Fetal rats were tolerized in utero with 10(5) Huh 7 cells. One day after birth, rats were transplanted with 5 x 10(6) Huh 7 cells and, a week later, inoculated with HCV, genotype 1. In tolerized, transplanted, and HCV-infected rats, Huh 7 cells were found in the liver, and HCV viral replication was detected by the presence of negative strand HCV RNA. HCV levels in serum were measured at 11,000 copies/mL at week 4, peaked at 22,500 copies/mL by week 12. In tolerized, transplanted, inoculated rats, but not controls, serum alanine aminotransferase (ALT) values increased to 60 IU/L by week 4 and reached a peak of approximately 120 IU/L by week 13. Histology showed foci of mononuclear infiltrates in portal and central regions. HCV-inoculated immunocompetent rats tolerized and transplanted with Huh 7 cells support HCV gene expression, viral replication, and develop biochemical and histologic evidence of hepatitis.

487 Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon α-2b therapy

Background and aims: Flares are a well known phenomenon during antiviral treatment for chronic hepatitis B. Little is known about the effect of flares on response. We investigated the timing and characteristics of flares, in relation to treatment response (hepatitis B e antigen loss). Patients: A total of 266 patients, participating in a global randomised controlled study, were assigned to 52wee ks of 100 μg pegylated (Peg)-interferon a-2b weekly, combined with either dai ly lamivudine 100 mg or placebo. Results: Sixty seven patients (25%) exhibited 75 flares, with 38 (51%) flares in the combination therapy and 37 (49%) in the monotherapy groups. Overall, 30%of patients with and 38%of patients without a flare responded to therapy (p = 0.25). In 24 patients (36%) the flare was foll owed by a decrease in hepatitis B virus (HBV) DNA (host induced flare). In 25 (3 8%) patients the flare was preceded by an increase in HBV DNA (virus induced fl are). In 17 (26%) patients the flare did not meet one of these criteria (indete rminate flare). Of patients with host induced flare, 58%responded whereas only 20%of patientswith virus induced flares responded (p = 0.008). Hepatitis B surf ace antigen loss (n = 8) was exclusively seen in patients experiencing a host in duced flare. Multivariate logistic analysis showed that host induced flares was an independent predictor of response (p = 0.043). Conclusion: Flares are not mor e common in responders than in non-responders to Peginterferon α-2b therapy. Virus induced flares, which occur after an increase in HBV DNA level, and most p robably are indicative for increased expression of viral antigens, did not lead to treatment response. In contrast, host induced flares which were followed by a HBV DNA decrease were highly associated with treatment response.

Acute flares in chronic hepatitis B: The natural and unnatural history of an immunologically mediated liver disease

Acute flares in chronic hepatitis B are common and may be caused by a number of identifiable and potentially treatable factors. The common link for many of these exacerbation episodes is a change in the immunologic response to hepatitis B virus (HBV), and this may have no identifiable cause or be triggered by an increase in viral replication or genotypic change. It is important to keep in mind the clinical situations in which patients are at increased risk of reactivated infection and secondary exacerbations. Reactivation is frequently induced by medical treatments such as cancer chemotherapy, antirejection drugs used in organ transplantation, and corticosteroids. The immunologic flares that often result from sudden withdrawal of these medications can be life-threatening unless recognized and treated promptly with antivirals, and there is increasing experience that preemptive antiviral treatment can diminish their occurrence and improve the outcome. The experience with lamivudine and other nucleoside analogues has increased our understanding of the molecular events behind hepatitis flares that occur when chronic hepatitis B is treated with drugs that potently inhibit HBV DNA polymerase. However, not all flares are explainable by events related to HBV infection alone. Depending on the population studied, as many as 20%–30% of flares may be caused by infection with other hepatotropic viruses, and this situation may inhibit HBV replication. Proper understanding of the etiology and effective treatment of acute flares in chronic hepatitis B requires an appreciation of high-risk clinical situations, assessment of HBV replication status, and testing for other viruses when appropriate.GASTROENTEROLOGY 2001;120:1009-1022

Superinfection by homotypic virus in hepatitis C virus carriers: Studies on patients with post-transfusion hepatitis

Although heterotypic superinfection and mixed infections of hepatitis C virus (HCV) may be possible for hepatitis flares in chronic hepatitis C, the possibility of homotypic HCV superinfection in HCV carriers with post-transfusion hepatitis has not been explored. Six HCV carriers with post-transfusion non-A, non-B hepatitis found in a prospective study of post-transfusion hepatitis were included. Serum samples before transfusion and during hepatitis were selected to determine genotypes of HCV and nucleotide sequences of the hypervariable region (HVR). The genotypes identified before and after transfusion were concordant in all. There were four with type 1b and one each with type 2a and type 2b. Amplified nucleotide sequences of the HVR before transfusion and during hepatitis were compared in four patients, and a > 95% homology was observed in three, suggesting persistence of original viruses. In contrast, only a 51% homogeneity was seen in a given patient, suggesting a homotypic HCV superinfection. Phylogenetic tree analysis validated further these findings. This study implies that HCV carriers can be reinfected by homotypic HCV, and this may contribute to hepatitis flares in chronic hepatitis C. These findings also confirm a weak or inadequate protective immunity in HCV infection and justify protection from reinfection of HCV of patients with chronic hepatitis C.