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Biomedical subjects

A S Lok

Publications and source records attributed to A S Lok.

At least 55 records · Page 3Linked to original sources
PubMed1995

Clinicopathological features of hepatitis C virus antibody negative fatal chronic hepatitis C after renal transplantation.

Clinical course and serial liver histology of a patient who developed fatal chronic active hepatitis C after renal transplantation are presented. This patient developed persistently deranged liver biochemistry 3 months after transplantation, despite normal liver enzyme values during the preceding 3 years on hemodialysis. In addition to increased parenchymal enzyme concentrations, the levels of ductal enzymes were also markedly elevated, with peak levels of alanine aminotransferase and gamma-glutamyl transpeptidase 7 and 100 times, respectively, the normal upper limit. The patient was persistently seronegative for hepatitis C virus (HCV) antibodies, but positive for HCV RNA. Treatment with alpha-interferon for 6 months, initiated after the development of early cirrhosis, resulted in no improvement, and the patient died from liver failure 36 months after renal transplantation. Serial liver histology, examined four times from 11 months to 36 months after transplantation, showed progressive deterioration from chronic active hepatitis to cirrhosis. This patient illustrates the uncommon complication of rapidly progressive and ultimately fatal liver disease due to HCV infection after renal transplantation. Early recognition with anti-HCV and HCV RNA assays as well as histologic assessment are crucial for the identification of patients with a poor prognosis who might benefit from therapeutic intervention before irreversible liver damage.

Adult↗
PubMed1995

Predictive value of precore hepatitis B virus mutations in spontaneous and interferon-induced hepatitis B e antigen clearance.

We previously reported two mutually exclusive mutations in the precore region of hepatitis B virus: M1 (T-1856, proline-serine substitution at codon 15) and M2 (A-1896, stop codon at codon 28). This study was conducted to determine if the presence of precore mutants affect spontaneous or interferon (IFN)-induced hepatitis B e antigen (HBeAg) clearance. Sera from 201 hepatitis B e antigen positive Chinese patients (including 106 who participated in a controlled trial of IFN therapy) with chronic hepatitis B virus (HBV) infection were analyzed by direct sequencing of HBV DNA after amplification by polymerase chain reaction (PCR) assay. Forty-three (21%) patients had M1 (T-1856), and 20 patients (10%) had M2 (A-1896). During a follow-up period of 1 to 7 years, 75%, 28%, and 26% of those with M2 (A-1896), M1 (T-1856), and wild type sequence respectively, cleared HBeAg (P < .0001). Eighteen (67%) of 27 patients with wild-type sequence but none of 10 patients who had M1 (T-1856) in their initial samples developed M2 (A-1896) after loss of HBeAg (P < .0001). Sustained antiviral response was achieved in 55%, 0%, and 17% of interferon-treated patients who had M2 (A-1896), M1 (T-1856), and wild-type sequence, respectively, initially (P = .04). However, patients with M2 (A-1896) were also more likely to have elevated pretreatment aminotransferase levels (P = .02). In summary, HBeAg-positive Chinese patients with M2 (A-1896) were mor likely to clear HBeAg, and to do so earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

Pathogenic role of hepatitis B virus in hepatitis B surface antigen-negative decompensated cirrhosis.

This study was conducted to determine the rate of detection of serum hepatitis B virus (HBV) DNA in hepatitis B surface antigen (HBsAg)-negative decompensated cirrhotic patients who had hepatitis B core and/or surface antibodies (anti-HBc and/or anti-HBs), and to compare the outcome of HBsAg-positive cirrhotic patients who did or did not clear HBsAg during follow-up. Six (5%) of 121 HBsAg-positive cirrhotic patients lost HBsAg after 0.2 to 17.1 years (mean, 9.1 +/- 6.2 yr) of follow-up. The cumulative rates of loss of HBsAg at 1, 5, 10, and 15 years were, respectively, 1.3%, 1.3%, 7.4%, and 44.5%. Compared with the patients who remained HBsAg-positive, those who lost HBsAg had milder disease at presentation and significantly longer survival. Of the patients who lost HBsAg, 83% had improvement in liver function after the loss of HBsAg, and all were alive at the time of writing (0.8 to 5.7 years after loss of HBsAg), whereas 27% of those who remained HBsAg-positive had died and 29% had deterioration in liver function. The rate of detection of serum HBV DNA by polymerase chain reaction (PCR) assay was higher in HBsAg-positive cirrhotic patients who lost HBsAg:67% versus cirrhotic patients who had no previous history of chronic HBV infection; 16% (cryptogenic) and 29% (hepatitis C virus and/or alcohol-induced liver disease). In summary, we found that using PCR, serum HBV DNA can be detected in 28% of HBsAg-negative cirrhotic patients who were studied, but the pathogenic significance of such small amounts of virus is not clear.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Naturally occurring hepatitis B virus core gene mutations.

Mutations in the hepatitis B virus (HBV) core gene may influence disease activity by altering immune recognition sites or level of virus replication. Sera from 69 Chinese patients with chronic HBV infection were analyzed by direct sequencing of polymerase chain reaction amplification of HBV DNA to determine the frequency and location of naturally occurring HBV core gene mutations. All but one patient had nucleotide changes, and 44 (64%) patients had at least one amino acid change (mean, 3.7; range, 1-13) when compared with published sequences. Multiple regression analysis showed that the frequency of core gene mutations was significantly associated with precore stop-codon mutation, hepatitis B e antigen negativity, and active liver disease, but not patients' age. The mean number of amino acid changes/patient for hepatitis B e antigen (HBeAg)-positive patients with elevated versus normal aminotransferase levels were, respectively, 2.8 +/- 0.4 and 0.6 +/- 0.2. The corresponding values for HBeAg-negative patients were, respectively, 5.0 +/- 1.2 and 6.0 +/- 1.5. Thirteen patients were serially studied, the mean rates of amino acid substitution in HBeAg-positive patients who did or did not clear HBeAg during follow-up were 5.7 +/- 0.8 and 0 per codon/yr. Most of the mutations were clustered in the codon/yr. Most of the mutations were clustered in the middle of the core gene that harbor several major B- and helper T-cell epitopes. Very few mutations were found in the C-terminal part of the core gene. In summary, mutations in the core gene can be frequently detected in patients with chronic HBV infection. These mutations occur predominantly around the time of HBeAg clearance when liver disease is most active.

Adolescent↗
PubMed1994

Clinicopathologic features of hepatitis C virus infection in renal allograft recipients.

The clinicopathologic features, the natural history, and the prognostic indicators of hepatitis C virus (HCV)-related liver disease in renal allograft recipients have not been well defined. Among 220 renal allograft recipients, 21 were seropositive for HCV RNA, which persisted on prospective follow-up for 40 months. Elevations in alanine aminotransferase and alkaline phosphatase were noted after renal transplantation in 15 (71.4%) and 9 (42.9%) patients, respectively, with 11 (52.4%) showing recurrent or persistent abnormalities. Mortality from liver failure was noted in 1 patient. Persistence of abnormal liver biochemistry was associated with an early onset of biochemical derangement after transplantation, and a longer dialysis duration (P < 0.05). HCV-related liver pathology was assessed in 13 patients by histologic scoring with respect to "hepatitic activity," "bile duct damage," and "architectural abnormality," adding up to a "total" score. Six (46.2%) of 13 initial liver biopsies showed significant chronic liver disease. Liver histology correlated with mean alanine aminotransferase and alkaline phosphatase levels after renal transplantation, and was more severe in patients with persistent biochemical abnormalities. Early onset of abnormal liver biochemistry after transplantation and persistently abnormal biochemistry were independent predictors of worse total and activity scores (P < 0.05). Renal transplant recipients demonstrated lower activity scores when compared with nonimmunosuppressed subjects with chronic hepatitis C (P = 0.03). HCV RNA was detectable in all 23 liver specimens tested. We conclude that significant, potentially life-threatening liver pathology manifests in about half of renal transplant recipients with chronic HCV infection. Liver histology correlates with the longitudinal biochemical profile. Patients with early onset of biochemical abnormalities and persistently deranged liver biochemistry are at risk of developing severe liver disease.

Adult↗
PubMed1994

Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal.

We conducted a large-scale survey to determine the frequency and clinical significance of mutations in the pre-core region of hepatitis B virus (HBV). Sera from 263 patients with chronic HBV infection were analyzed by direct sequencing of PCR-amplified HBV DNA. Four major missense/nonsense mutations (M) were found: (M1) C-->T at nucleotide position 1856, Pro-->Ser at codon 15; (M2) G-->A at position 1896, Trp-->stop at codon 28; (M3) G-->A at position 1898, Gly-->Ser at codon 29; and (M4) G-->A at position 1899, Gly-->Asp at codon 29. The commonest conserved mutation was M0: T-->C at position 1858, Pro-->Pro at codon 15. We found that M1 and M2 were mutually exclusive, M3 was only found in association with M1, and M4 was predominantly found in association with M2. All patients with M1 but none of those with M2 had M0. The invariable coexistence of certain mutations in codon 15 and codons 28 and 29 and the mutual exclusion of other mutations in these two noncontiguous regions is related to the stem-loop structure of the pre-genome encapsidation sequence located in the precore/core region. M2 and M4 enhance the stability of the stem by providing two additional paired sites. M1 destroys an existing base pair. However, M1 only occurred in the presence of M0, which provides an extra paired site, and 50% of patients with M1 had M3, a compensatory mutation that restores base pairing at this site. Our data support the proposed secondary structure of the pre-genome encapsidation sequence. The primary function of the mutations in the pre-core region is to enhance stability of this secondary structure to ensure perpetuation of viral replication.

Base Sequence↗
PubMed1994

Treatment of chronic hepatitis B.

Chronic infection with the hepatitis B virus (HBV) is a major cause of worldwide morbidity and mortality. A large number of therapeutic approaches has been tried, including interferon (IFN), nucleoside analogues and immunomodulators. To date controlled clinical trials have shown that only IFN is of long-term value but many patients fail to respond to treatment. New approaches to treating patients with IFN-resistant hepatitis B are currently undergoing clinical and experimental evaluation, and it seems likely that new therapeutic agents will be available in the near future.

Antiviral Agents↗
PubMed1994

Comparative study of three doses of interferon-alpha 2a in chronic active hepatitis B. The International Hepatitis Trial Group.

To determine the efficacy of interferon-alpha 2a in chronic active hepatitis B, 238 patients were randomly divided, into four groups: three groups received either 2.5 MIU m-2, 5.0 MIU m-2 or 10.0 MIU m-2, three times weekly by intramuscular injection for 12-24 weeks; and a control group received no treatment. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV-DNA)] between treated and untreated patients (37 vs 13%) but no statistically significant difference was seen between treatment groups (33%, 34% and 43% for the 2.5, 5.0 and 10.0 MIU m-2 groups, respectively). A transient rise in transaminases (seroconversion hepatitis) was seen in responders, but levels returned to within the normal range after response to treatment. In patients responding to interferon therapy there was a significant reduction in the severity of the hepatitis. Interferon-alpha 2a was generally well tolerated with respect to vital signs and laboratory parameters.

Adolescent↗
PubMed1994

Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members.

Precore hepatitis B virus mutants have been detected mainly in HBeAg-negative patients with active liver disease. We previously reported two novel mutations: M1 (C-to-T change at nucleotide 1856 [proser at codon 15]) and M3 (G-to-A change at nucleotide 1898 [gly-ser at codon 29]) in addition to two well-described mutations: M2 (G-to-A change at nucleotide 1896 [trp-stop at codon 28]); and M4 (G-to-A change at nucleotide 1899 [gly-asp at codon 29]) in Chinese patients. The aims of this study were to determine (a) the prevalence of precore HBV mutations in asymptomatic carriers and (b) whether family members share the same mutated sequence as the index patients. Fifty-three index patients and 89 HBsAg-positive family members were studied by means of direct sequencing of polymerase chain reaction-amplified hepatitis B virus DNA. M0, a conserved mutation (T-to-C at nucleotide 1858, codon 15), was detected in 81% and 12% family members of index patients with and without M0, respectively (p < 0.0001). The clustering of M0 indicates that most subjects were infected through intrafamilial transmission. M1 was detected in all the family members of patients with M1 but in none of the family members of patients with wild-type or M2 sequences (p < 0.0001). M2 was detected in 25%, 0% and 15% of family members of patients with M2, M1 and WT sequences, respectively (p = 0.19). M3 was detected in five and M4 in four family members.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Longitudinal study of hepatitis C viremia in chronic hepatitis C.

Serial serum samples from 20 untreated patients with chronic hepatitis C virus (HCV) infection were tested for HCV RNA by a nested polymerase chain reaction assay using primers from the highly conserved 5' noncoding region to determine the relationship between hepatitis C viremia and the activity of liver disease during the natural course of chronic HCV infection. Semiquantitation of serum HCV RNA level was achieved by testing serial 10-fold dilutions of RNA extracts to determine the end-point titer. All the patients were HCV RNA positive at presentation. There was a poor correlation between the initial HCV RNA titer and serum transaminase levels. All patients except one were persistently HCV RNA positive during a follow-up period of 1.5-15 years, although 17 (85%) had periods of normal or near-normal transaminase levels. There was no correlation between changes in the serum transaminase levels and HCV RNA titer. Patients with chronic HCV infection have persistent viremia despite fluctuations in ALT levels.

Adult↗
PubMed1993

A prospective study of hepatitis C virus infection among renal transplant recipients.

BACKGROUND: Chronic non-A, non-B hepatitis is a major cause of liver disease in renal transplant recipients. METHODS: One hundred eight-five renal allograft recipients, including 151 who had been prospectively followed up for 24 months, were studied to determine the prevalence and course of hepatitis C virus (HCV) infection. Antibody to HCV (anti-HCV) was measured by enzyme immunoassay, and HCV RNA was measured by nested polymerase chain reaction assay. RESULTS: Twenty-three (12.4%) patients were positive for anti-HCV and/or HCV RNA: 19 (10.3%) were anti-HCV positive; and HCV RNA was detected in 18 (94.7%) anti-HCV-positive and 4 (2.4%) anti-HCV-negative patients. Markers of HCV infection persisted in all HCV-positive patients over the 2-year period. Most HCV-positive patients acquired HCV infection before or at the time of transplantation. The incidence of new infection after transplantation was 0.45% per patient-year. Anti-HCV and/or HCV RNA was detected in 75% of patients with biochemical chronic non-A, non-B hepatitis, but transaminase levels were persistently normal in 30.4% of HCV-positive individuals. CONCLUSIONS: HCV infection is common among renal transplant recipients. Testing for HCV RNA is important because some patients might not produce anti-HCV. Transaminase levels cannot be used as a surrogate marker of HCV infection in these patients.

Adult↗
PubMed1993

Long-term follow-up of chronic hepatitis B patients treated with interferon alfa.

BACKGROUND: There is very little data on the long-term outcome of patients with chronic hepatitis B after interferon therapy. A 6-year follow-up of two interferon trials in chronic hepatitis B patients is reported. METHODS: One hundred twenty-eight Chinese adults with chronic hepatitis B who received interferon therapy were followed for 19-79 months (median 41 months). Twenty-nine patients lost hepatitis B e antigen and two also lost hepatitis B surface antigen within 1 year of treatment. RESULTS: Seven (24%) responders reactivated. Twenty-eight (28%) nonresponders had sustained clearance of hepatitis B e antigen during follow-up. Delayed clearance of hepatitis B e antigen occurred more frequently in nonresponders who had elevated pretreatment serum transaminase levels. (P = 0.002). Serum hepatitis B virus DNA became undetectable by polymerase chain reaction assay in both responders who lost hepatitis B surface antigen but in only 8 (17%) patients who lost hepatitis B e antigen only. Delayed clearance of hepatitis B surface antigen was not seen in any of the 48 patients who had sustained clearance of hepatitis B e antigen. CONCLUSIONS: Contrary to reports from Western countries, complete elimination of markers of hepatitis B virus infection was uncommon in Chinese patients with chronic hepatitis B who underwent interferon therapy despite similar duration of follow-up.

Adult↗
PubMed1993

Re-evaluation of alpha-interferon treatment of chronic hepatitis B using polymerase chain reaction.

To re-evaluate the efficacy of 3 treatment trials involving 272 Chinese patients with chronic hepatitis B virus infection, serial serum samples were tested from 60 patients treated with alpha-interferon with or without prednisone priming and 12 control patients, who were negative for hepatitis B virus deoxyribonucleic acid using dot-blot hybridization. Serial samples were tested using nested polymerase chain reaction with primer sets chosen from the surface and core antigen coding regions. The 19 patients who did not show persistent serological change remained hepatitis B virus deoxyribonucleic acid positive using the polymerase chain reaction assay. Three of the 4 patients (75%) who lost hepatitis B surface antigen and 9 of 51 (17.6%) who lost hepatitis B e antigen became negative from 0 to 60 months after the e-seroconversion. All patients negative for the polymerase chain reaction assay had normal transaminase levels. Pooling the 3 trials together, 11 of 188 (5.9%) treated patients and 1 of 84 (1.2%) control patients became hepatitis B virus deoxyribonucleic acid negative. The difference was not statistically significant. As assayed by the polymerase chain reaction assay, patients who were treated with alpha-interferon with or without steroid priming and lost hepatitis B e antigen within 12 months were more likely to subsequently lose the virus completely from the serum (11 of 33) than those who lost hepatitis B e antigen after 12 months (none of 13; p = 0.029).

Base Sequence↗