Uncomplicated Acute Hepatitis Research Articles

Temporal profile of HEV RNA concentration in blood and stool from patients with acute uncomplicated hepatitis E in a region with genotype 1 predominance.

Acute hepatitis E virus (HEV) is associated with viremia and faecalexcretion of the virus. The information on duration and temporal pattern of viremia and faecal shedding in HEV infection is important, but is not available. Serial serum and stool specimens were collected from patients with acute hepatitis E (typical clinical picture, serum alanine aminotransferase levels>5-folds the upper limit of normal and presence of IgM anti-HEV), beginning from within 7days of the onset of symptoms. HEV RNA concentrations were measured in sera and 10% stool suspensions, using a real-time Taqman-based nucleic acidamplification assay. Seventeen patients (median age 25 [range 19-61] years; all men) were enrolled within a median of 5 (range 3-8) days of the onset of the first symptom and provided 113 serum specimens and 71 stool specimens. The median (range) highest levels of serum bilirubin, alanine aminotransferase and aspartate aminotransferase in the patients were 10.3 (5.9-43.4) mg/dL, 1817 (442-4642) IU/L and 1016 (88-4561) IU/L, respectively. All the 17 patients had demonstrable viremia, and 12 of the13 patientswho were tested had faecal excretion at one or more time points. The HEV RNA titres were the highest in the early phase of disease and declined rapidly with time, becoming nondetectable in the serum by day 20 and in thestool by day 21. In most of the patients with acute uncomplicated acute hepatitis E, the degree of viremia and faecal shedding decline quickly after the onset of clinical illness and rapidly disappear in parallel with each other.

Subacute Hepatic Failure: Its Possible Pathogenesis

Background: Subacute hepatic failure (SAHF) is a complicationof acute hepatitis (AH) characterized by progressive jaundiceand development of ascites within 24 weeks of the onset oficterus. Its pathogenesis is unknown and its treatment isunsatisfactory. This study highlights on the possiblepathogenesis of the disease.Materials and methods: Thirty-two with SAHF among 798patients of AH who had tests for markers of acute hepatitis A,B, C and E had blood and ascitic fluid study and ultrasonogram(US) of liver. US and risk factors for infection were comparedwith consecutive uncomplicated AH. Blood culture was done inconsecutive 307 AH patients at the time of the first visit. Patientswith SAHF and control were followed for at least 6 months.Results: SAHF developed in 4% of the patients with AH.Bacteremia was detected in 50% and ascitic fluid showedfeatures of hepatic venous outflow obstruction (HVOO) andbacterial peritonitis. Thrombus was detected in IVC in all.Seventy-five percent of the patients who received antibioticrecovered. Recurrence of the symptoms in five and developmentof cirrhosis in seven patients were noted at follow-up but noneamong patients with uncomplicated acute hepatitis (AH).Bacteremia was also detected in 25% of consecutive AHpatients presenting with fever, with high incidence in those withcomplications.Conclusion: Bacteremia was common among patients withAH. Clinical features of SAHF could be explained by occurrencesuperadded bacterial infection that caused thrombophlebitis ofhepatic portion of the IVC resulting in HVOO.Abbreviations: AHF: Acute hepatic failure; CH: Chronichepatitis; AH: Acute hepatitis; SAHF: Subacute hepatic failure;ULN: Upper limit of normal; ALT: Alanine aminotransferase;AP: Alkaline phosphate; HA: Hepatitis A; HB: Hepatitis B; HC:Hepatitis C; HE: Hepatitis E; HVSC: Hepatic vena cavasyndrome; US: Ultrasonography; IVC: Inferior vena cava; LPS:Lipopoly sachcharides; BN: Bridging necrosis; HVOO: Hepaticvenous outflow obstruction.

Integration of hepatitis B virus DNA into chromosomal DNA during acute hepatitis B

To examine the serum from black African patients with acute hepatitis B to ascertain if integrants of viral DNA can be detected in fragments of cellular DNA leaking from damaged hepatocytes into the circulation. DNA was extracted from the sera of five patients with uncomplicated acute hepatitis B and one with fulminant disease. Two subgenomic PCRs designed to amplify the complete genome of HBV were used and the resulting amplicons were cloned and sequenced. HBV and chromosomal DNA were amplified from the sera of all the patients. In one patient with uncomplicated disease, HBV DNA was integrated into host chromosome 7 q11.23 in the WBSCR1 gene. The viral DNA comprised 200 nucleotides covering the S and X genes in opposite orientation, with a 1 169 nucleotide deletion. The right virus/host junction was situated at nucleotide 1,774 in the cohesive overlap region of the viral genome, at a preferred topoisomerase I cleavage motif. The chromosomal DNA was not rearranged. The patient made a full recovery and seroconverted to anti-HBs- and anti-HBe-positivity. Neither HBV nor chromosomal DNA could be amplified from his serum at that time. Integration of viral DNA into chromosomal DNA may occur rarely during acute hepatitis B and, with clonal propagation of the integrant, might play a role in hepatocarcinogenesis.

Nitric oxide and pro-inflammatory cytokines in acute hepatitis B

Background: Experimental studies demonstrate that hepatitis B virus may induce nitric oxide (NO) production in infected hepatocytes. Its presence in acute hepatitis B patients has not been studied. Methods: Serum levels of nitric oxide and its regulatory pro-inflammatory cytokines were detected in 15 patients with uncomplicated acute hepatitis B, 19 blood donors and 15 chronic hepatitis B patients. Cytokines were determined with an immunoassay. Nitric oxide was measured as the serum metabolic products of nitrates and nitrites using a modification of the Griess reaction. Results: All detected cytokines were increased in acute hepatitis B patients compared to healthy controls ( p<0.001 for TNF-α, p<0.05 for IL-6, p<0.001 for IL1-β and p<0.001 for IFN-γ). High serum levels of nitric oxide were found in acute hepatitis B patients (156.96±9.76 μmol/l) compared to healthy controls (51±6.2 μmol/l, p<0.001) and chronic hepatitis B patients (63.97±3.78 μmol/l, p<0.001). No significant correlations were found between NO, cytokine levels and transaminases. Conclusions: High levels of nitric oxide and its regulatory cytokines were found in a group of patients with uncomplicated acute hepatitis B. The exact role of NO in the disease pathogenesis and outcome needs to be studied further.

Hepatitis B: clinical manifestations, diagnosis and medical management

The author reviews the history, symptoms and signs of acute hepatitis B and its differential diagnosis. Special emphasis is laid on its natural history and the discussion of uncomplicated acute hepatitis B, fulminant hepatitis and chronic HBV infection.

Southwestern Internal Medicine Conference: Hepatitis B — Molecular Variants with Clinical Significance?

Mutations in the DNA of the hepatitis B virus have been discovered and they may have clinical significance. A single nucleotide substitution resulting in a premature stop codon in the pre-core region of the hepatitis B genome is the most common change. The premature stop codon prevents the synthesis of hepatitis B e antigen (HBeAg), a virally encoded protein normally secreted by hepatocytes. The mutant hepatitis B virus was initially discovered in patients who lacked HBeAg in the serum yet had high levels of hepatitis B viral DNA, a marker of active viral replication usually found in association with the continued presence of HBeAg. Other studies demonstrated that the mutant forms were observed with increasing frequency during the successful conversion from HBeAg positivity to anti-hepatitis B e antibody (anti-HBe) positivity. The mutant form of hepatitis B virus was not identified in patients with stable chronic hepatitis B who were positive for HBeAg or in any patients with uncomplicated acute hepatitis B, regardless of the presence of HBeAg or anti-HBe. However, mutant hepatitis B virus was detected in patients with fulminant hepatitis B who lacked both HBeAg and anti-HBe. The lack of HBeAg in the serum therefore may result in a more severe form of acute disease. Together with experimental animal studies of the normal role of HBeAg, these data suggest that serum HBeAg may be associated with immunologic tolerance, whereas clearance of or lack of HBeAg may be associated with an active immunologic response. Future studies are expected to clarify the role of mutant forms of hepatitis B virus in the natural history of hepatitis B infection.

Monoclonal Antibody Recognizing Pre‐S(2) Epitope of Hepatitis B Virus: Characterization of Pre‐S(2) Epitope and Anti‐Pre‐S(2) Antibody

A hybrid cell line producing monoclonal antibodies recognizing an epitope encoded by the pre-(S)2 region of hepatitis B virus (HBV) genome was obtained by fusion of mouse myeloma cells with lymphocytes from mice immunized with HBV. The monoclonal antibody Mo-F124 secreted from the hybrid line reacted with the pre-S(2) epitope expressed on the surface of both viral and recombinant HBsAg particles--pre-S(2) and S gene product--localised on 34 kD glycoprotein of the viral envelope. The pre-S(2) epitope was sensitive to digestion with V8 protease from Staphylococcus aureus. The enzyme abolished reactivity with Mo-F124 and polymerized human serum albumin (pHSA) binding activity of recombinant particles. Mo-F124 antibody was used to develop highly sensitive radioimmunoassays for determination of pre-S(2) epitope and anti-pre-S(2) antibody in sera of hepatitis B patients. Detection of a pre-S(2) epitope by the monoclonal antibody-based assay in the early phase of acute HBV infection correlated well with the presence of markers of active viral replication (HBeAg, HBV DNA). The appearance of anti-pre-S(2) antibody, usually in the third month after onset of symptoms, was followed by elimination of circulating HBsAg and seroconversion to anti-HBs in all tested cases of uncomplicated acute hepatitis followed by recovery. Anti-pre-S(2) response was not observed in patients with chronic hepatitis B or acute HBV infection progressing to chronic disease. The observed correlation of anti-pre-S(2) response with recovery suggests that the pre-S(2) epitope may represent one of the epitopes inducing antibodies that neutralize the hepatitis B virus.

Prognostic significance of piecemeal necrosis in acute viral hepatitis.

The predictive value of piecemeal necrosis (PMN) in acute hepatitis was investigated in 62 patients (39 hepatitis B virus infection, 9 hepatitis A virus infection and 14 possible hepatitis NANB virus infection). The 62 initial biopsies were blindly recoded and classified into three groups: 1. Acute hepatitis with signs of possible transition to chronicity (AHTC) (n = 35) (i.e. a picture of acute hepatitis associated with PMN). 2. AHTC-borderline group (BL) (n = 15) (i.e. a picture of acute hepatitis with minimal PMN). 3. Uncomplicated acute hepatitis (AH) (n = 12) (i.e. a picture of acute hepatitis without PMN). Follow-up of the patients revealed an evolution to chronicity in a very high percentage of the AHTC-cases of hepatitis B (95%) and NANB (89%) etiology. Also 67% of the BL-cases of hepatitis B etiology developed chronic liver disease. In hepatitis B the immunohistochemical pattern of HBsAg is of additional help. In hepatitis A, PMN is often present (5/9) but no evolution to chronicity was observed. This study shows that PMN in acute hepatitis appears to be a useful prognostic feature for chronicity in hepatitis B and NANB.

Virus-Associated Receptors for Polymerized Human Serum Albumin in Acute and in Chronic Hepatitis B Virus Infection

The receptor for polymerized human albumin, recently identified on the hepatitis B virus, was studied by hemagglutination in 89 patients with acute and chronic hepatitis B virus infection. The receptor, which was differentiated from antialbumin antibodies by immunofluorescence and hemagglutination inhibition, was detected mainly in patients with active virus replication, independently of hepatitis B surface antigen titer. Thirteen of 20 uncomplicated acute hepatitis B cases were positive at clinical onset (mean log2 titer +/- SD: 4.20 +/- 2.46) but became negative during the acute phase, while 5 patients who progressed to chronic hepatitis had significantly higher receptor titers at onset (7.0 +/- 0.0, p less than 0.01) and remained positive afterwards. In chronic hepatitis B virus infection, the receptor was detected in 17 of 30 patients with chronic active hepatitis, in 5 of 12 with chronic persistent hepatitis, and in 2 of 16 healthy carriers. Among hepatitis B e antigen positive cases a wide range in receptor levels was observed, and in longitudinal studies most patients with low initial titers seroconverted to hepatitis B e antibody while patients with higher titers remained persistently hepatitis B e antigen positive. These results indicate that the virus receptor for polyalbumin may represent a useful marker in hepatitis B e antigen positive acute and chronic hepatitis B.

IgM antibody to the hepatitis B core antigen in acute hepatitis determined by SPRIA--diagnostic value.

A solid phase radio-immunoassay (SPRIA) was developed for the detection of anti-HBc IgM. The assay proved sensitive and easy to perform and rheumatoid factor did not affect the test results. Anti-HBc IgM titres were followed in consecutive samples from 15 patients after uncomplicated acute hepatitis B. In the acute phase anti-HBc IgM titres ranged from 10(-5) to 10(-7) (mean 10(-6.4)). One year after onset of disease ten of the 15 had titres below 10(-4) and between two and three years after onset most patients had titres 10(-3). Anti-HBc IgM titres were determined in six episodes of acute hepatitis B, all HBsAg negative but anti-HBc positive in the first samples obtained (within 8 days) and developing anti-HBs during convalescence. Acute phase anti-HBc IgM titres in these patients ranged between 10(-5.5) and 10(-7) (mean 10(-6.5)) and were thus identical with HBsAg positive cases. When acute phase sera from 168 episodes of acute hepatitis primarily classified as non-A, non-B, were tested for anti-HBc IgM titres above 10(-5), sera from 13 episodes were positive and in seven of these hepatitis B diagnosis could be confirmed by rising anti-HBs titres in convalescence. Sera from four of the 13 patients contained HBeAg, which was thus demonstrated in the absence of HBsAg. The results show that testing for anti-HBc IgM is important for a true non-A, non-B diagnosis.

Anti-LSP antibodies in acute liver disease.

Sera from 71 patients with acute liver injury have been tested for antibodies to hepatocyte membrane lipoprotein complex (LSP) using a sensitive radioimmunoassay. Two main patterns of anti-LSP response were seen. In the first, seen in patients with type A and B viral hepatitis, anti-LSP antibodies were detectable at presentation, with the highest titres two to 10 days before the peak in serum aminotransferases and, in the hepatitis B patients, when viral DNA polymerase concentrations were still high, indicating active viral replication. These findings are consistent with the anti-LSP response being consequent on an interaction between T cells and neoantigens on the liver cell surface. A similar pattern was found in halothane hepatitis where immune responses to a halothane-altered liver membrane antigen are present early in the course of the disease. In the second type of response, exemplified by cases with paracetamol-induced hepatic necrosis, anti-LSP was only occasionally detectable at presentation, although present in very low titre later in the clinical course. This may be due to the release of altered antigen at the time of hepatocellular injury. The same pattern was found in a selected group of patients with uncomplicated acute alcoholic hepatitis, suggesting that in both these groups of patients the liver damage may have been due to a direct toxic effect on liver cells.

Anti‐HBc of IgM‐class, HBeAg and anti‐HBe in acute and chronic hepatitis B

The presence and persistence of IgM antibody against hepatitis B core antigen (anti-HBc IgM) and the correlation with other HBV markers were studied in 42 patients, all of whom had acute HBsAg-positive hepatitis but whose subsequent diseases differed. All patients initially had anti-HBc IgM. In 13 out of 15 patients with uncomplicated acute hepatitis, anti-HBc IgM disappeared within 6 months after onset of the disease. In five out of 12 patients, who in spite of transient HBsAg developed chronic liver disease, the anti-HBc IgM persisted for more than 2 years. Among 15 patients with persistent HBsAg, anti-HBc IgM was present from 7 months to more than 8 years. Seroconversion from HBeAg to anti-HBe was observed in seven patients and in five of these anti-HBc IgM disappeared during the follow-up period. These results indicate that anti-HBc IgM can be used as a serological marker of recent or ongoing HBV infection.

Functioning liver mass in uncomplicated and fulminant acute hepatitis.

The galactose elimination capacity and the plasma clearance of phenazone were investigated in 24 patients with uncomplicated acute hepatitis and in 8 patients who survived and in 26 who died of fulminant hepatitis. The galactose elimination capacity was 52% of the normal mean value on admission to the hospital in uncomplicated hepatitis, 47% in patients who survived fulminant hepatitis, and 22% in the fatal cases, while the plasma clearance of phenazone was 43%, 22%, and 10%, respectively. Both quantitative liver function tests showed rapid improvement in most cases of uncomplicated acute hepatitis and in the patients who survived fulminant hepatitis. They did not improve in the fatal cases of fulminant hepatitis, among whom the patients with the lowest initial values died first. Both the galactose elimination capacity and the plasma clearance of phenazone were significantly higher in survivors than in non-survivors of fulminant hepatitis. The results indicate that the loss of functioning liver cell mass is about 60-70% in the acute stage of uncomplicated hepatitis and 80-85% in patients who survive fulminant hepatitis, whereas patients who die of fulminant hepatitis have nearly total loss of functioning liver cell mass.

Hepatic morphologic findings and viral antigens in acute hepatitis B

In the course of a prospective clinical study, 26 liver biopsies were taken in 24 previously healthy patients with an uncomplicated acute hepatitis B (AHB) and a subsequent complete recovery (UR group). Serum transaminase levels were used to distinguish four AHB stages, as the variability in duration made time dependent staging less appropriate. As a reference, a second group of 22 liver biopsies from 7 patients from the same prospective clinical study who eventually developed chronic hepatitis (CH group) was included. Due to fluctuations of transaminase levels in this group the stages two and three could not be separated, stage four was not reached within the follow-up period of median 5 years. Histopathological criteria and the distribution patterns of hepatitis B surface (HBsAg) and core (HBcAg) antigens were studied. Piecemeal necrosis and bridging hepatic necrosis were a frequently occurring feature in the liver biopsies of the UR group taken during the stage of peak transaminase levels. In this respect, no differences could be demonstrated between the UR group and the CH group. The occurrence of these features in AHB thus appears to have no prognostic value as risk factor for chronic liver disease. In contrast, diffuse cytoplasmic (‘ground glass’) HBsAg localization was only found in stage 2/3 of the CH group. It is concluded that apart from ground glass cells, care must be taken to interpret any histopathological feature in AHB as risk factor of progression to chronicity without reference to the duration of illness. The possible significance regarding the host's immune mechanisms of some features that may persist during chronic liver disease is discussed.

Changes in hepatitis B virus DNA polymerase in relation to the outcome of acute hepatitis type B.

Serum levels of hepatitis B virus specific DNA polymerase and hepatitis B e antigen were studied serially in 34 patients with hepatitis B virus infection--20 who had the acute illness and recovered, seven who died with fulminant disease, three who died as a result of subacute hepatic necrosis, and four who went on to develop chronic active hepatitis. DNA polymerase activity was present in 16 (80%) and HBeAg in 13 (65%) of the uncomplicated cases at presentation and in all of those patients from whom the initial sample was obtained before the peak in aminotransferase. Both markers disappeared after 30 days from the onset but DNAP remained persistently positive during a follow-up period of four to 10 months in the four patients who progressed to chronic hepatitis. These results indicate that DNAP and HBeAg are transiently present in all cases of acute hepatitis B. Only their persistence after the acute episode could represent a useful prognostic marker of chronically. In this respect, DNAP was more reliable in our patients than HBeAg. In uncomplicated acute hepatitis, the peak in DNAP levels, which defines the time of maximum virus replication in the liver, preceded the peak in aminotransferase levels. Among the 10 patients who developed massive liver damage after hepatitis B infection, DNAP was detected in five of the seven with fluminant hepatitis, with enzyme levels that were comparable with those observed in uncomplicated acute hepatitis and presentation, but not in the cases of subacute hepatic necrosis. These findings are consistent with the hypothesis that in hepatitis B infection, liver damage, whatever the severity, is not directly related to the degree of virus replication.

Quantitative studies of Australia antigen in acute and chronic hepatitis. Evidence for an inverse relationship between circulating Au-antigen and transaminase values in patients with progression from acute to chronic hepatitis.

Abstract. Quantitation of circulating Australia antigen (Au‐antigen) was performed by electrophoresis in antibody‐containing gel, using a modification of the method of Laurell [7], on consecutive serum specimens from 19 patients with uncomplicated acute viral hepatitis associated with transient Au‐antigenaemia, and from 9 patients with persistence of Au‐antigen and histological progression from acute to chronic hepatitis. None of the patients received corticosteroids or other immunosuppressive drugs. In all cases in the group of patients with uncomplicated acute hepatitis, an exponential fall in the Au‐antigen concentration was observed. In the group of patients with persistent antigenaemia, two phases of the disease were observed. Initially, these patients showed great variations in both the Au‐antigen concentration and in the serum glutamic oxalacetic transaminase activity (SGOT). An inverse relationship between the Au‐antigen concentration and the transaminase values was observed. The next phase, 1–2 years after onset of the disease, was characterized by low values of the Au‐antigen concentration and low SGOT activity.

Differential distribution of Australia-antigen-associated particles in patients with liver diseases and normal carriers.

Electron microscopy of Australia antigen particles was carried out on 80 serum specimens from 42 patients with various liver diseases and from six "normal" carriers. Dane particles were found in the serum of 11 of 13 patients with persistent antigenemia and chronic hepatitis, but in only seven of 24 patients with uncomplicated acute hepatitis and transient antigenemia. No Dane particles were found in the specimens of six healthy carriers. The ratio between the small spherical particles and the rod-shaped particles was on an average 18.4 in patients with uncomplicated acute hepatitis and 3.8 in those with persistent antigenemia and chronic hepatitis. In eight patients serum samples were available from both the acute and the chronic phase of hepatitis, and, initially, the particle-pattern was similar to the pattern seen in patients with chronic hepatitis. Thus, electron microscopy of Australia antigen particles in serum may be of prognostic value in acute hepatitis.

Quantitative Studies of Australia Antigen in Acute and Chronic Hepatitis

Quantitation of circulating Australia antigen (Au-antigen) was performed by electrophoresis in antibody-containing gel, using a modification of the method of Laurell [7], on consecutive serum specimens from 19 patients with uncomplicated acute viral hepatitis associated with transient Au-antigenaemia, and from 9 patients with persistence of Au-antigen and histological progression from acute to chronic hepatitis. None of the patients received corticosteroids or other immunosuppressive drugs. In all cases in the group of patients with uncomplicated acute hepatitis, an exponential fall in the Au-antigen concentration was observed. In the group of patients with persistent antigenaemia, two phases of the disease were observed. Initially, these patients showed great variations in both the Au-antigen concentration and in the serum glutamic oxalacetic transaminase activity (SGOT). An inverse relationship between the Au-antigen concentration and the transaminase values was observed. The next phase, 1-2 years after onset of the disease, was characterized by low values of the Au-antigen concentration and low SGOT activity.

Haptoglobin in children with infectious hepatitis

Serum haptoglobin levels were determined several times during the course of the disease in children with infectious hepatitis. At the onset of uncomplicated acute hepatitis the serum haptoglobin is in the normal range. There is a significant temporary rise in serum haptoglobin during the recovery stage of the disease, after which it returns to normal. The absence of this rise or the fall of serum haptoglobin below normal level are unfavorable prognostic signs, indicating the transition of the disease to the subacute or chronic form. Serum haptoglobin levels were determined several times during the course of the disease in children with infectious hepatitis. At the onset of uncomplicated acute hepatitis the serum haptoglobin is in the normal range. There is a significant temporary rise in serum haptoglobin during the recovery stage of the disease, after which it returns to normal. The absence of this rise or the fall of serum haptoglobin below normal level are unfavorable prognostic signs, indicating the transition of the disease to the subacute or chronic form.