Long-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients.

UNLABELLED: Exclusive monotherapy with zinc in symptomatic Wilson disease is controversial. Seventeen symptomatic patients with Wilson disease were treated with zinc only. The mean age at diagnosis and start of treatment was 18 years (range 13-26) with approximately half presenting as adolescents. Presentation was exclusively hepatic, exclusively neurologic, and combined in seven, five, and five patients, respectively. The median follow-up was 14 years (range 2-30). At baseline, two of the 12 patients with hepatic disease exhibited decompensated cirrhosis, five exhibited compensated cirrhosis, and five had less severe disease. Both patients with decompensated cirrhosis improved to a compensated state after initiation of therapy. Two of the five patients with initial compensated cirrhosis progressed to decompensated state, and three remain stable. Three of the five patients with moderate or mild liver disease remain stable and two improved. Apart from decreasing bilirubin levels, no significant changes occurred in the liver biochemistry or function during long-term follow-up. Nine of 10 neurologic patients improved markedly and one deteriorated. Two patients with exclusively neurologic presentation developed liver disease during zinc treatment. Two patients with exclusively hepatic presentation developed mild neurologic symptoms. According to 24-hour urinary copper excretions (213 +/- 38 versus 91 +/- 23 microg: P = 0.01) and serum non-ceruloplasmin-bound copper concentrations (11 +/- 2 versus 7 +/- 1 microg/dL: P = 0.1) at the end of follow-up, the efficacy of decoppering was less in the exclusively hepatic than in the neurologic group. The prescribed zinc dose and 24-hour urinary zinc excretions tended to be less in the exclusively hepatic group. CONCLUSION: The outcome of exclusive zinc therapy is generally good in cases of neurologic disease. A less satisfactory outcome in hepatic disease may relate to less efficient decoppering.

Should hepatitis B vaccination be introduced into childhood immunisation programmes in northern Europe?

Infection with hepatitis B causes between 500,000 and 1.2 million deaths per year worldwide, and is the leading cause of liver cancer. Over 12 years ago, WHO recommended that universal childhood hepatitis B vaccination be implemented globally. Despite this, Denmark, Finland, Iceland, Ireland, the Netherlands, Norway, Sweden, and the UK have yet to implement such a policy and instead currently adopt an "at-risk" strategy. Although all eight countries are classed as having low endemicity, factors such as increased travel and integration of immigrant communities are increasing the number of at-risk individuals in these countries. Considering the difficulty in identifying all at-risk individuals, and the lack of effectiveness of at-risk vaccination on reducing the overall incidence of hepatitis B, we recommend that these countries reassess their hepatitis B prevention strategies. Universal vaccination against hepatitis B is the only way to eliminate the major public-health impact of this disease.

UVB exposure impairs immune responses after hepatitis B vaccination in two different mouse strains.

Ultraviolet light exposure can impair immune responses that are not restricted to the exposed skin but is also found at other sites, i.e. systemic immunosuppression. Therefore, we investigated the UV-induced modulating effects on vaccination against hepatitis B in a mouse model. Two different mouse strains, BALB/c and C57B1/ 6, were vaccinated intramuscularly against hepatitis B. Mice were exposed to different doses of ultraviolet B (UVB) for five consecutive days on shaved back skin before the vaccination. Vaccination against hepatitis B induced cellular (delayed-type hypersensitivity [DTH] and lymphocyte stimulation test) as well as humoral immune responses in both mouse strains. The DTH responses in C57BB1/6 mice were statistically significantly higher compared with BALB/c mice. UVB exposure induced a dose-dependent suppression of cellular immunity in both strains of mice. C57B1/6 mice seemed to be more susceptible to this suppression. Anti-hepatitis B surface antibodies (total-Ig) were only marginally suppressed after UVB exposure. IgG2a and interferon-gamma levels, both indicators for Th1 immune response, were suppressed in both mouse strains after UVB exposure. In summary, UVB exposure induced a dose-dependent suppression of both cellular and humoral immune responses after hepatitis B vaccination, although the suppressive effects on humoral immunity were limited to IgG2a production. Susceptibility to UVB-induced immunomodulation depended on the strain of mice and their predilection for developing different T cell responses.

Epidermal cis-urocanic acid levels correlate with lower specific cellular immune responses after hepatitis B vaccination of ultraviolet B-exposed humans.

Urocanic acid (UCA) is a major UV-absorbing chromophore in the epidermis and has been suggested to act as one of the initiators of UV-induced immunosuppression. cis-UCA, the isomer from UCA that is formed upon UV exposure, has been shown to impair some cellular immune responses. cis-UCA levels were determined in a study in which the influence of ultraviolet B (UVB) exposure on immune responses after hepatitis B vaccination in human volunteers was established. A significant increase in cis-UCA levels was found in the skin of UVB-exposed volunteers compared with controls. cis-UCA levels, calculated as the percentage of the total UCA amount, in UVB-exposed volunteers correlated significantly with the cumulative UVB dose received in 5 consecutive days, i.e. the higher the UVB dose (J/m2), the higher the cis-UCA levels (until a cis-UCA plateau was reached in the so-called photostationary state). Correlations between skin cis-UCA levels and immune responses were determined, and they revealed no statistically significant correlations among lymphocyte proliferation responses after either mitogenic stimulation or stimulation with recall antigens. No correlation was found between cis-UCA levels and hepatitis B-specific antibody titers. However, we found a statistically significant negative correlation between cis-UCA levels and hepatitis B-specific lymphocyte proliferation responses when volunteers were irradiated with UVB before hepatitis B vaccination. In other words, volunteers with high cis-UCA levels caused by UVB exposure showed lower cellular immune responses against hepatitis B antigen after hepatitis B vaccination.

Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899].

BACKGROUND: Since esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. METHODS: 166 patients with esophageal varices grade II, III of IV according to Paquet's classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs. RESULTS: During a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk. CONCLUSION: In the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver cirrhosis and a low to moderate bleeding risk. Although sclerotherapy lowered mortality attributable to variceal bleeding, overall survival was not affected. The effect of prophylactic sclerotherapy seems dependent on the underlying bleeding risk. A beneficial effect can only be expected for patients with a high risk for bleeding.

Long-term persistence of T cell memory to HBsAg after hepatitis B vaccination.

AIM: To determine if the T cell memory to HBsAg can persist for a long time after hepatitis B (HB) vaccination. METHODS: Thirty one vaccine recipients who were healthcare workers (18 females and 13 males aged 34-58 years) from Utrecht University Hospital, Netherlands, and had previously received a standard course of vaccination for hepatitis B were investigated and another 9 unvaccinated healthy volunteers from the same hospital were used as the control. Blood samples were taken just before the experiment to test serum anti-HBs levels and the subjects were classified into different groups according to their serum titers of anti-HBs and vaccination history. Their peripheral blood mononuclear cells (PBMC) were isolated from freshly heparinized venous blood and the proliferative response of T lymphocytes to the recombinant hepatitis B surface antigen (HBsAg) was investigated. RESULTS: Positive serum anti-HBs was found in 61.3% (19/31) vaccine recipients and a significant in vitro lymphocyte proliferative response to recombinant HBsAg was observed in all the vaccinees with positive anti-HBs. Serum anti-HBs level < or =10 IU/L was found in 38.7% (12/31) subjects. In this study, we specially focused on lymphocyte proliferative response to recombinant HBsAg in those vaccine recipients with serum anti-HBsAg less than 10 IU/L. Most of them had received a standard course of vaccination about 10 years before. T lymphocyte proliferative response was found positive in 7 of the 12 vaccine recipients. These results confirmed that HBsAg-specific memory T cells remained detectable in the circulation for a long time after vaccination, even when serum anti-HBs level had been undetectable. CONCLUSION: The T cell memory to HBsAg can persist for at least 10 years after HB vaccination. Further booster injection is not necessary in healthy responders to HB vaccine.

Is a low dose of hepatitis B vaccine enough for a rapid vaccination scheme?

AIM: To determine whether or not a low dose of HB vaccine can be effectively used in the rapid vaccination. METHODS: Rapid vaccination (0, 1, 2 months) with low dose (5 microg) or routine dose (10 microg) HB vaccine was studied in 250 subjects (130 school children and 120 university students). Serum from all the participants was tested for HBsAg, anti-HBs and anti-HBc at 1, 3 and 7 months after the first dose of vaccination and all subjects were serum HBV marks negative before the vaccination. Non-responders to a complete initial vaccination from university students were given an additional vaccination with 10 microg of HB vaccine and their serum anti-HBs was tested again one month later. RESULTS: One month after the third dose of vaccination (third month) sero-conversion rates and geometric mean titer (GMTs) were significantly (P<0.01) higher in the routine dose (resp. 89% and 106.8) than in the low dose group (resp. 72% and 59.5). Sero-conversion rates and GMTs were maintained stable for another 4 months in both groups. After an additional vaccination to non-responders with 10 microg HB vaccine, 17/23 subjects (13/15 from those vaccinated with 5 microg vaccine and 4/8 from those vaccinated with 10 microg vaccine) became anti-HBs positive, yielding similar sero-conversion rates for both dose groups. CONCLUSION: Higher sero-conversion rates and GMTs were reached in those vaccinated with 10 microg HB vaccine than in those vaccinated with 5 microg HB vaccine after a complete vaccination with a 0, 1, 2 month scheme. But the subjects vaccinated with 5 microg vaccine can also reach the similar sero-conversion rate after an additional vaccination.

Transmission profile of hepatitis B virus infection in the Batam region, Indonesia. Evidence for a predominantly horizontal transmission profile.

The aim of this study was to describe the distribution of hepatitis B virus markers among the autochthonous and immigrant multicultural populations of Riau province, Indonesia, in order to define the groups at risk and their infrastructure. This investigation was part of a large hepatitis B vaccination study. A total of 9701 healthy individuals, aged 5 years or older and living in the urbanised area of Batam, near Singapore, and on the surrounding islands were included. Socio-epidemiological data were collected, blood was drawn, and sera were tested for antibodies to hepatitis B core (anti-HBc) and surface antigen (anti-HBs). Anti-HBc-positive sera were tested against hepatitis B surface antigen (HBsAg). All tests comprised immunoassays from Roche (Germany) using Elecsys 2010. Complete data were available from 9314 subjects. The results showed relatively low prevalences of anti-HBc (a marker of a previous hepatitis B infection) and HBsAg in the 5-year-old chiLdren (5.8 and 1.9%, respectively) that increased continuously with increasing age. High anti-HBs levels (>1000 IU/L) were found in all age cohorts, indicating a lifelong threat of active hepatitis B infection. In conclusion, the transmission profile of hepatitis B appeared to be mainly horizontal (person-to-person) in the highly endemic region studied. Vertical transmission was less than 5%. The horizontal transmission routes included non-sexual activities of life since children <10 years of age also showed considerable infection rates. The results underline the need for catch-up hepatitis B vaccination programs for children and adults.

Exploratory study on the effects of treatment with two mistletoe preparations on chronic hepatitis C.

Twenty-one patients with chronic hepatitis C were treated with a mistletoe preparation as monotherapy (either Iscador or Abnoba viscum) during one year. The treatment was well tolerated. Patients entering the study with elevated transaminases had a significant improvement, both for AST (aspartate aminotransferase) (p = 0.01) and for ALT (alanine aminotransferase) (p = 0.04). Quality of life significantly improved (p = 0.006) in patients with a low initial quality of life. Although one patient obtained a complete virological response, few effects on viral load were seen in the whole group. These results suggest an effect comparable to glycyrrhicin treatment: improvement of liver inflammation and thus possibly reduction of the long term complications, viz cirrhosis and liver cancer. Mistletoe preparations have the advantage of easy administration and low cost.

Cytokine polymorphisms play a role in susceptibility to ultraviolet B-induced modulation of immune responses after hepatitis B vaccination.

UVB exposure can alter immune responses in experimental animals and humans. In an earlier human volunteer study, we demonstrated that hepatitis B-specific humoral and cellular immunity after vaccination on average were not significantly affected by UVB exposure. However, it is known that individuals differ in their susceptibility to UVB-induced immunomodulation, and it was hypothesized that polymorphisms in specific cytokines may play a role in this susceptibility. In this respect, we previously demonstrated that immune responses after hepatitis B vaccination are influenced by the minor allelic variant of IL-1 beta in the general population. For all volunteers, single nucleotide polymorphisms were determined for the following UV response-related cytokines: IL-1 receptor antagonist (+2018), IL-1 alpha (+4845), IL-1 beta (+3953), TNF-alpha (-308), and TNF-alpha (-238). Exposure to UVB significantly suppressed Ab responses to hepatitis B in individuals with the minor variant for the IL-1 beta polymorphism. Increased minimal erythema dose values (just perceptible), which resulted in higher absolute UVB exposures, were observed in the same individuals. There were no associations observed between UVB-induced immunomodulation and the other cytokine polymorphisms examined. This study indicates that individual susceptibility to UVB radiation needs to be considered when studying the effects of UVB in humans.

Reduction of relapse rates by 18-month treatment in chronic hepatitis C. A Benelux randomized trial in 300 patients.

BACKGROUND/AIMS: Treatment of chronic hepatitis C with interferon can be ineffective due to relapse. We aimed to reduce the 40% relapse rate of 6 months interferon-ribavirin combination therapy by prolonging treatment to 18 months. METHODS: Three hundred patients with treatment-naive hepatitis C, were randomized to 18 months combination therapy with interferon (3MU tiw) and ribavirin (1000-1200 mg/day), 18 months interferon combined with placebo, or 6 months combination therapy with interferon and ribavirin, in a double blinded manner. All 295 patients who received at least one dose of treatment were included in the intention to treat analysis. RESULTS: At the end of treatment, HCV RNA was undetectable in 55 and 49% of those on 6 and 18 months combination therapy, respectively, versus 26% of those on monotherapy (P<0.001). The relapse rate was 38% for 6 months combination therapy, 38% for 18 months monotherapy, and only 13% for 18 months combination treatment (P=0.002). The sustained response rates were 34% for 6 months combination therapy, 16% for 18 months monotherapy and 43% for 18 months combination therapy (P<0.05). CONCLUSIONS: Reduction of relapse rates to 15% or less is feasible by prolongation of interferon-ribavirin treatment to 18 months.

The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis.

BACKGROUND AND AIMS: Wilson disease is an hereditary disorder of copper metabolism, caused by mutations in the ATP7B gene, and leading to hepatic or neurologic disease. We examined whether H1069Q, the most common ATP7B mutation, is associated with a specific phenotype. METHODS: Genotyping results in 70 Dutch patients were related to clinical presentation. Subsequently a meta-analysis for genotype-phenotype correlation was performed on all patients available from literature, combined with the current Dutch group, a total of 577 patients. RESULTS: The Dutch patients homozygous or heterozygous for the H1069Q mutation presented more frequently with neurologic disease (63% and 43% vs. 15%), and at a later age (20.9 and 15.9 vs. 12.6 years) than patients without the H1069Q mutation. In the meta-analysis the odds-ratio for neurologic presentation in homozygous or heterozygous H1069Q vs. non-H1069Q patients was 3.50 (95% CI 2.01-6.09) and 2.13 (95% CI 1.18-3.83), respectively. Age at presentation was 21.1, 19.2 and 16.5 years, respectively, corresponding to a weighted mean difference (WMD) of 4.41 (95% CI 1.56-7.26) for homozygous H1069Q vs. heterozygous patients and 6.68 (95% CI 4.33-9.38) for homozygous H1069Q vs. non-H1069Q patients. CONCLUSIONS: Our results indicate that the H1069Q mutation is associated with a late and neurologic presentation.

IL-1beta gene polymorphisms influence hepatitis B vaccination.

Considerable variability exists in the vaccine response to hepatitis B with 5-10% of healthy young adults demonstrating no or inadequate responses following a standard vaccination schedule. As the interleukin-1beta (IL-1beta) cytokine has been shown to be important in the development of immune responses, we determined whether vaccine efficacy is influenced by genetic polymorphisms associated with IL-1beta expression. Ninety-two healthy individuals who were negative for antibodies to hepatitis B antigen (anti-HBs) were vaccinated against hepatitis B according to a standardized schedule. At selected times, antibody titers and lymphoproliferative capacity to hepatitis B surface antigen (HBsAg) were determined. DNA genotyping for IL-1beta polymorphisms using a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique demonstrated that both the anti-HBs titer and the T-cell lymphoproliferative response to HBsAg are significantly increased in individuals possessing the IL-1beta (+3953) minor allelic variant.