Two cases of colon LST in transplanted liver patients.

Long-life immunosuppressive therapy increases the risk of de novo tumors in liver transplant recipients by decreasing the immune surveillance against malignant cells and oncogenic viruses. However, no cases of colon precancerous lesions have been reported in these subjects. Patient n. 1, a 73 yrs old male treated with calcineurin and purine synthesis inhibitors, showed at a per-protocol colono-scopy a 3 cm laterally spreading tumor (LST). Patient n. 2, a 73 yrs old male treated with calcineurin inhibitors, showed at a screening colonoscopy an LST occupying one third of the lumen circumference. Both subjects were asymptomatic, had been transplanted 14 years before, and in both cases, lesions showed severe dysplasia. LSTs represent 17.2% of advanced colorectal neoplasia (CRC) and risk factors are multifactorial. Immunosuppression may play a role which is however not completely understood. Based on this report, surveillance colonoscopy in liver transplanted patients should be considered.

Adefovir dipivoxil-associated thrombocytopenia in a patient with chronic hepatitis B.

A 56-year-old male patient received adefovir dipivoxil (10 mg/day) for chronic hepatitis B resistant to lamivudine. On the fifth week of treatment, the platelet count dropped to 26 x 10(3) mm(-3); anti-platelet antibodies were detectable in serum. The drug was discontinued and the platelet count improved spontaneously. A re-challenge with adefovir caused a new episode of thrombocytopenia, again after a five-week treatment period. To date, thrombocytopenia has not been described after adefovir therapy for chronic hepatitis B and seems to be a rare event.

Innate and acquired immune system in patients developing interferon-alpha-related autoimmune thyroiditis: a prospective study.

OBJECTIVE: In this prospective study, we investigated whether the development of interferon (IFN)-alpha-related autoimmune thyroiditis (IFN-AT) was correlated with the sequential changes of cytokine pattern induced by IFNalpha in the peripheral lymphocytes. PATIENTS AND METHODS: We enrolled 18 hepatitis C virus (HCV)-positive patients who developed IFN-AT, eight patients with euthyroidism [IFN-AT(Eu)] and 10 with thyroid dysfunction [IFN-AT(Dy)]. Twenty HCV-positive patients without IFN-AT acted as control group (Co-HCV+). Intracellular expression of IFNgamma and IL-4 was evaluated by multicolor flow-cytometry analysis in peripheral lymphocytes in vitro stimulated by phorbol-12-myristate-13-acetate (PMA) (25 ng/ml) and ionomycin (1 mug/ml) in presence of monensin (5 microm). RESULTS: At the appearance of thyroid disease, both IFN-AT(Eu) and IFN-AT(Dy) patients showed a significant increase of IFNgamma expression in CD3+CD56+ and CD3-CD56+ cells but not in CD4+ and CD8+ cells. At this time point, IFN-AT(Eu) but not IFN-AT(Dy) patients also showed an increase of IL-4 expression in CD3+CD56+ cells and CD4+ cells. Six months later, IFN-AT(Eu) patients maintained high expression of IL-4 in CD4+ and CD3+CD56+ cells without any further increase in IFNgamma expression. By contrast, IFN-AT(Dy) patients showed an increase of IFNgamma expression in CD4+ and CD8+ cells, with a concomitant decrease of IL-4 expression in CD4+ cells. CONCLUSIONS: Type 2 immune response is activated early and specifically in patients with IFN-AT who remain euthyroid throughout the follow-up. Predominant in patients developing thyroid dysfunction, by contrast, is the type 1 immune response that seems to occur earlier in innate than acquired immune system.

Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in 'real world' patients with chronic hepatitis C.

BACKGROUND: Interferon-alpha plus ribavirin therapy for chronic hepatitis C is associated with adverse effects that lead to therapy discontinuation in up to 27% of patients in randomized controlled trials. AIM: To examine the causes and predictive factors for therapy discontinuation in patients treated in current clinical practice. METHODS: We retrospectively enrolled 441 consecutive patients, scheduled to receive interferon-alpha + ribavirin for chronic hepatitis C, in five centres. Patients had been treated with 3 or 6 MU interferon-alpha three times a week plus ribavirin, 800-1200 mg daily, for 6 or 12 months. RESULTS: One hundred and eight [24.5%; confidence interval (CI), 20.5-28.8%] patients failed to finish combination therapy because of adverse events. The discontinuation rate was higher during the first 6 months of treatment; anaemia was an important cause (36.1% of discontinuations); unexplained lipothymia resulted in discontinuation in 11 patients. Female gender [hazard ratio (HR) = 1.85; CI, 1.17-2.92], an interferon-alpha dose > 15 MU/week (HR = 1.79; CI, 1.12-2.86) and no previous interferon-alpha treatment (HR = 1.63; CI, 1.04-2.57) were independent factors associated with discontinuation. The simultaneous presence of these factors identified patients at high risk for discontinuation [odds ratio (OR) = 10; CI, 3.98-25.13]. CONCLUSIONS: The study identified some predictive factors for adverse event-related discontinuation, which may improve the safety profile and effectiveness of interferon-alpha + ribavirin combination therapy in chronic hepatitis C.

Temporal relationship between the appearance of thyroid autoantibodies and development of destructive thyroiditis in patients undergoing treatment with two different type-1 interferons for HCV-related chronic hepatitis: a prospective study.

In this prospective study we performed repeated evaluations of thyroid status in patients undergoing treatment with different preparations of recombinant interferons (IFNs), in order to identify early markers of thyroid dysfunction. Moreover, we aimed to investigate whether the development of thyroid dysfunction was related to the appearance of thyroid autoimmunity. Our study included 51 consecutive patients without pre-existing thyroid disease, admitted to our hospital for Hepatitis C virus (HCV)-related chronic hepatitis. Thirty-six patients (Gr. A) were treated with IFN-alpha 2b plus ribavirin (RIBA), whereas 15 patients (Gr. B) underwent treatment with IFN-alphacon-1 (CIFN) plus RIBA. Thyroid autoimmunity and function were prospectively evaluated before, every month during treatment and for 6 months after IFN withdrawal. At study entry, all patients were euthyroid and negative for thyroid autoantibodies. In Gr. A, 10 patients developed thyroid autoimmunity after a median period of 3 months (range: 1-6) treatment with IFN-alpha+RIBA. At the time of appearance of thyroid autoantibodies, 4 patients developed destructive thyrotoxicosis (overt in one case, subclinical in 3 cases), while other 4 patients showed a high reduction of serum TSH levels (median decrease: -75.7%, range: -61.9- -84.2), which reached the low values of normal range. After a median period of 2 months (range: 1-3) from these biochemical abnormalities, 6 patients continuing antiviral treatment developed hypothyroidism (overt in 3 cases and subclinical in the other 3). In Gr. B, 5 patients developed thyroid autoimmunity after a median period of 3 months (range: 2-10) of treatment with CIFN+RIBA. Soon after the appearance of thyroid autoantibodies, all patients developed an overt thyrotoxicosis (with hyperthyroidism in 2 cases). Antiviral treatment was discontinued in all 5 cases. Thereafter, thyroid function recovered spontaneously without significant modifications of serum TGAb and TPOAb levels until the end of the study. In conclusion our prospective study demonstrated that: 1) the appearance of thyroid autoantibodies during treatment with IFN was accompanied in most cases by the occurrence of a destructive process in the thyroid gland; 2) The clinical expression of destructive thyroiditis was more evident in patients treated with CIFN than that in patients treated with IFN; 3) The thyroid clinical outcome of these patients was strictly correlated to the continuation of cytokine treatment.

Isolated autoimmune response: definition, analysis of the prevalence in an outpatient rheumatology clinic, relationship to pre-clinical autoimmune disease and infections by hepatotropic viruses.

OBJECTIVE: To define the clinical significance of non-organ specific autoantibody positivity in patients in whom routine clinical and laboratory examinations did not detect any disease that might have caused the serological finding. METHODS: Out of 1,120 patients consecutively admitted to an outpatient rheumatology clinic, 28 were referred for the evaluation of an autoantibody positivity unrelated to the clinical status. These patients and 28 sex- and age-matched controls underwent a specific work-up with the aim of detecting any underlying infection or autoimmune disease. RESULTS: Eight of the 28 patients (28.5%) were found to be affected by a previously undetected disease: 3 chronic hepatitis C, 3 Sjögren's syndrome, and 2 autoimmune thyroiditis. The remaining 20 did not show any autoimmune or hepatic disease, although 4 of them showed active infection by HBV (n = 1) or HGV (n = 3) and 15 had had a previous infection by hepatotropic viruses (HBV, CMV or EBV). After a follow-up lasting 6-54 months, none of the last 20 patients developed any autoimmune or chronic hepatic disease. CONCLUSIONS: A diagnostic work-up is necessary in patients presenting with unexpected autoantibody positivity in order to detect an underlying pre-clinical autoimmune disease and/or unexpected hepatic infection. Patients in whom such a work-up fails to point out any condition should be further followed in order to make an early diagnosis of autoimmune disease.

Quantitative viremia test for early prediction of a biochemical response in patients with chronic hepatitis C treated with interferon.

To evaluate the importance of the changes in viremia as an early predictor of the outcome of interferon (IFN) therapy, we assayed the levels of hepatitis C virus (HCV)-RNA in stored serum samples obtained from 34 patients with chronic hepatitis C who showed different biochemical responses to therapy. Serum samples obtained before the start of therapy and after 1 and 3 months were used, and viremia levels were determined by "branched DNA (bDNA)" technique. Viremia levels at 1 month of therapy were lower than pre-therapy levels in all 19 patients who had shown a persistent normalization of ALT during therapy (responder patients). The bDNA test was negative, i.e. the levels of viremia were below the sensitivity threshold of the method, in 12 (63.1%) patients at 1 month and in 13 (68.4%) at the 3rd month of therapy, whereas the bDNA test was negative in none of the 15 non-responder patients at the 1st month and in only 2 (13.3%) of them at the 3rd month of therapy. The bDNA test was superior to the ALT test both in predicting the non-response and the biochemical response to IFN after 1 month of therapy. The bDNA test results, instead, were not predictive of the duration of the response to IFN, either at the 1st or 3rd months of therapy. These results seem to indicate the usefulness of measuring the HCV-RNA levels at the beginning and after 1 month of IFN therapy in order to envisage or exclude a possible biochemical response early on in treatment.

Interferon-alpha plus amantadine in chronic hepatitis C resistant to interferon alone: a pilot randomized study.

The optimal therapy for patients with chronic hepatitis C who have not responded to interferon (IFN) is still an unsolved issue. The aim of this study was to evaluate the efficacy and tolerability of a high dose of IFN-alpha2a plus amantadine for chronic hepatitis C patients who were non-responders to a previous course of IFN. Forty consecutive patients with chronic hepatitis C, genotype 1b, who had not responded to IFN-alpha, were randomized to receive: (i) IFN 4.5 MU daily plus amantadine 200 mg/day for 4 weeks and then IFN 6 MU thrice weekly plus amantadine 200 mg/day for an additional 5 months (group A) or (ii) IFN alone at the same dosage and duration (group B). After 1 month of therapy, normal alanine aminotransferase (ALT) values were observed in three of 21 (14.3%) patients in group A and in three of 19 (15.8%) in group B; serum hepatitis C virus (HCV)-RNA clearance was observed in one patient (4.8%) in group A and in six (31.6%) in group B. At the end of treatment, six patients (28.6%) in group A and three (15.8%) in group B had normal ALT levels; however, HCV-RNA in serum was detectable in all of them at levels comparable to the basal values; an ALT relapse occurred within 3 months of stopping therapy. The combination of daily IFN plus amantadine was ineffective in this setting.

Type B and D viral hepatitis: epidemiological changes in Southern Europe.

The incidence of hepatitis B virus (HBV) and hepatitis D virus (HDV) infection is in rapid decline in Southern Europe, due to the improvement in hygiene and economic conditions and the vaccination campaigns against hepatitis B. These changes have led to a shift from the classic form of chronic hepatitis B due to the wild-type virus, expressing hepatitis B e antigen (HBeAg) to a liver disease due to a mutated virus which does not express the HBeAg (e-minus mutant). Very interestingly, HBV-DNA has been detected in the liver tissue and in the serum of some subjects who lack hepatitis B surface antigen (HBsAg) in serum. This "occult" infection may be responsible for the residual cases of acute hepatitis B and might influence the course of chronic liver diseases of different aetiologies. A further consequence of the control of HBV infection is a spectacular decline in HDV circulation. At present only 8% of the HBsAg carriers in Italy have anti-HDV antibodies, vs 23% in 1987. Most of the patients with HDV infection are over 40 and present a mild liver disease or a slowly progressive cirrhosis. These epidemiological data support the concept that the epidemiological changes influence the clinical pattern of chronic hepatitis.

Chronic hepatitis D: a vanishing Disease? An Italian multicenter study.

Hepatitis delta virus (HDV) was responsible for a high proportion of cases of acute and chronic liver disease in Southern Europe during the 1970s. Some data suggest that by the 1990s HDV circulation had substantially declined. We have assessed the prevalence of HDV infection and its clinical impact in 834 Italian hepatitis B surface antigen (HBsAg) carriers in 1997. Anti-HDV antibodies were sought in all consecutive chronic HBsAg carriers observed in 14 referral liver units throughout Italy. Risk factors for anti-HDV positivity were evaluated. Anti-HDV antibodies were found in 69 of 834 (8.3%) HBsAg-positive patients. Cohabitation with an anti-HDV-positive subject, intravenous drug addiction, residence in the South of the country, and the presence of cirrhosis were independently associated with the presence of anti-HDV antibodies. The overall prevalence of anti-HDV antibodies was lower than those observed in 2 multicenter surveys performed in 1987 and 1992 (23% and 14%, respectively). By 1997, the percentage of anti-HDV-positive subjects had sharply decreased in the 30 to 50 years age group, whereas it was almost unchanged in subjects over 50 years of age. The highest prevalence of anti-HDV antibodies (11.7%) was found in patients with cirrhosis. This prevalence was as high as 40% in the 1987 study. The circulation of HDV sharply decreased in Italy, by 1.5% per year, from 1987 to 1997. This decrease resulted mainly from the reduction in chronic HDV infections in the young, for whom high morbidity and mortality rates were recorded in the past. The results anticipate the almost complete control of HDV infection in the near future.

[Elevata prevalenza ma bassa incidenza della infezione da HGV in pazienti con epatite cronica C] / Elevata prevalenza ma bassa incidenza della infezione da HGV in pazienti con epatite cronica C.

Objectives To determine 1. The prevalence and incidence of HGV infection in patients with chronic hepatitis C and 2. Its influence on the clinical outcome of chronic hepatitis C. Patients and methods Sixty-five patients with non-parenteral chronic hepatitis C virus infection were investigated for HGV infection using the polymerase chain reaction for HGV-RNA and by detecting serum antibodies against the E2 protein of HGV (anti-E2 antibodies). Results HGV-RNA in serum was found in 12 patients (18.4%) and anti-E2 antibodies in 4 (6.1%). No difference in age, sex, liver histology, basal ALT or ?GT was found between HGV positive and negative cases. Thirty-four patients (6 with HGV-RNA) were followed-up for 4 years; 4 of the 6 lost HGV-RNA, one of whom seroconverted to anti-E2. None of the 28 HGV-RNA negative cases presented HGV infection during the follow-up period. The presence of HGV infection did not influence either basal HCV viremia or the response of HCV to IFN therapy. Conclusions The study demonstrated that HGV had an intense circulation through non-classic parenteral routes, but its impact on HCV replication and liver disease is negligible.

Human leucocyte interferon-alpha in chronic hepatitis C resistant to recombinant or lymphoblastoid interferon-alpha: a randomized controlled trial.

Patients with biopsy-proven chronic hepatitis C, who failed to respond to a previous course of either recombinant (rIFN-alpha) or lymphoblastoid (Ly IFN-alpha) interferon-alpha, were randomized to receive either leucocyte (Le) IFN-alpha (patients) or a second course of the same IFN-alpha (controls), to compare the efficacy and safety of these treatment schedules. All patients received the same dose of IFN-alpha as was used during their previous treatment (3 million units (MU) or 6 MU three times weekly) for 6 months. Patients with a normal alanine aminotransferase (ALT) value at month 6 were treated for a further 6 months. All patients were followed-up for 12 months after treatment. A total of 69 patients were enrolled, 44 in the Le IFN-alpha group and 25 in the control group. At the end of the treatment period, 13 of the 44 patients (29.5%) in the Le IFN-alpha group had a biochemical response (normal ALT) and six of 44 (13.6%) patients had undetectable serum hepatitis C virus (HCV) RNA. At the end of the follow-up period, 10 patients (22.7%) had normal ALT values and serum HCV RNA was undetectable in three (6.8%). None of the patients in the control group showed normal ALT values at any time. Genotype 1b tended to be more frequent among non-responders (61 vs 45%): basal gamma-glutamyl transpeptidase (gamma-GT) values were lower in responders than in non-responders (33.3 +/- 11.70 Ul-1 vs 58.4 +/- 33.04; P = 0.01). Le IFN-alpha was well tolerated by all patients. These results support the use of Le IFN-alpha in patients with chronic hepatitis C who are non-responders to a previous treatment with recombinant or lymphoblastoid IFN-alpha.