Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

Liver stiffness measurement reliability and main determinants of point shear-wave elastography in patients with chronic liver disease.

BACKGROUND: Liver stiffness (LS) measured by transient elastography (TE) accurately predicts the severity of chronic liver diseases (CLD). Point quantification shear-wave elastography (pSWE) is a new technique incorporated into a conventional ultrasound system for measuring LS. We evaluated pSWE feasibility, reproducibility and diagnostic accuracy in consecutively recruited CLD patients who concomitantly underwent TE and liver biopsy. AIM: To evaluate pSWE feasibility, reproducibility and diagnostic accuracy in consecutively recruited CLD patients who concomitantly underwent TE and liver biopsy. METHODS: Over 2 years 186 CLD patients (116 males, 132 viral hepatitis) consecutively underwent pSWE (10 valid measurements by ElastPQ) blindly performed by two raters. A further operator performed TE. Inter-observer agreement for pSWE was analysed by intraclass correlation coefficient (ICC) and correlated with histological liver fibrosis (METAVIR). Main determinants of pSWE were investigated by linear regression model. RESULTS: Three hundred and seventy-two (100%) reliable measurements were obtained by pSWE and 184 by TE (99%). LS was 8.1 ± 4.5 kPa for pSWE with the first rater and 8.0 ± 4.2 kPa with the second one vs. 8.8 ± 3.6 kPa for TE. pSWE ICC was 0.89 (95% CI 0.85-0.91), not influenced by age, sex, BMI, liver enzymes, liver aetiology. ICC increased over time with year 1 at 0.86 and 95% CI 0.81-0.90 vs. year 2 at 0.92 and 95% CI 0.87-0.95. Liver fibrosis was the only independent determinant of LS on pSWE. The AUROCs for diagnosing F ≥ 2, F ≥ 3 and F = 4 were 0.77, 0.85 and 0.88 for pSWE vs. 0.81, 0.88 and 0.94 for TE. After 1-year training they were 0.86, 0.94 and 0.91. CONCLUSION: Point quantification shear-wave elastography reliably and reproducibly evaluates liver stiffness, matching transient elastography for accuracy after a 1-year learning curve or 130 examinations.

Serum autoantibodies against cytochrome P450 2E1 (CYP2E1) predict severity of necroinflammation of recurrent hepatitis C.

We previously reported that autoantibodies against cytochrome P4502E1 (CYP2E1) are frequent in patients with chronic hepatitis C. As autoimmune reactions are increasingly detected after orthotopic liver transplantation (OLT), this study investigates prevalence and significance of anti-CYP2E1 autoantibodies in 46 patients with post-OLT recurrent hepatitis C. IgG against recombinant human CYP2E1 above the control threshold was detected in 19 out 46 (41%) sera collected immediately before OLT and in 15 out 46 (33%) sera collected at the time of the 12 months follow-up liver biopsy. Although anti-CYP2E1 reactivity was not modified by OLT, the patients with persistently elevated anti-CYP2E1 IgG (n = 12; 26%) showed significantly higher prevalence of recurrent hepatitis with severe necroinflammation and fibrosis than those persistently negative or positive only either before or after OLT. Moreover, the probability of developing severe necroinflammation was significantly higher in persistently anti-CYP2E1-positive subjects. Multivariate regression and Cox analysis confirmed that the persistence of anti-CYP2E1 IgG, together with a history of acute cellular rejection and donor age >50 years, was an independent risk factor for developing recurrent hepatitis C with severe necroinflammation. We propose that autoimmune reactions involving CYP2E1 might contribute to hepatic damage in a subgroup of transplanted patients with recurrent hepatitis C.

ERCP and short-term stent-trial in patients with anastomotic biliary stricture following liver transplantation.

BACKGROUND: Anastomotic biliary stricture represents one of the possible factors leading to liver dysfunction after transplantation. PURPOSE: Our aims were to evaluate the role of endoscopic retrograde cholangio-pancreatography and a short-term stenting (stent-trial) in assessment of the clinical relevance of the biliary stricture. MATERIALS AND METHODS: Thirty transplanted patients for HCV (n=17) or non-HCV (n=13)-related cirrhosis (27M, median age 53 yr, range 24-67 yr) who developed persistently abnormal liver function tests and presented with an anastomotic biliary stricture suggested by non-invasive cholangiography, underwent endoscopic retrograde cholangio-pancreatography. If the stricture was confirmed, dilation was performed and a plastic stent was placed. Clinical and biochemical evaluation was done one and two months later. Resolution of symptoms and normalization or > 50% reduction of at least one liver function test were needed to consider the stricture as clinically relevant. Patients were followed up for a median of 19 months. RESULTS: Endoscopic retrograde cholangio-pancreatography was successful in 29 patients and confirmed the anastomotic biliary stricture in 19 (66%); 14 patients underwent endoscopic dilation and stenting and five patients underwent surgery. The stent-trial suggested the stricture to be clinically relevant in 7 of 14 patients, confirmed by prolonged stenting and follow-up. A trend towards a higher likelihood of a clinically relevant stricture was observed in HCV-negative compared to HCV-positive patients (5 of 7, 71% vs 2 of 7, 29% , respectively; p=0.1). CONCLUSIONS: Our data suggest that endoscopic retrograde cholangio-pancreatography is a valuable tool to evaluate the clinical relevance of an anastomotic stricture, when coupled with a short-term stent-trial.

Transient elastography predicts fibrosis progression in patients with recurrent hepatitis C after liver transplantation.

OBJECTIVE: Transient elastography (TE) allows non-invasive evaluation of the severity of liver disease in patients with chronic hepatitis C. This procedure, however, warrants further validation in the setting of liver transplantation (LT), including patients under follow-up for recurrent hepatitis C. SETTING: Tertiary referral hospital. PATIENTS: 95 patients (75 males) transplanted for end-stage liver disease due to hepatitis C virus. INTERVENTIONS: Paired liver biopsy (LB) and TE were carried out 6-156 (median, 35) months after LT. 40 patients with recurrent hepatitis C sequentially evaluated 6-21 months apart. MAIN OUTCOME MEASURES: Clinical, laboratory and graft histological features influencing TE results. RESULTS: Median TE values were 7.6 kPa in the 90 patients with a successful TE examination, being 5.6 kPa in the 30 patients with Ishak fibrosis score (S) of 0-1, 7.6 kPa in the 38 with S2-3; 16.7 kPa in the 22 with S4-6, (p < 0.0001). Areas under the ROC curves were 0.85 (95% CI, 0.76 to 0.92) for S > or = 3, 0.90 (95% CI, 0.82 to 0.95) for S > or = 4 with 7.9 and 11.9 kPa optimal TE cut-off (81% and 82% sensitivity, 88% and 94% negative predictive value, respectively). Fibrosis, necroinflammatory activity and higher than 200 IU/l gamma-glutamyl transpeptidase levels independently influenced TE results. During post-LT follow-up, TE results changed in parallel with grading (r = 0.63) and staging (r = 0.71), showing 86% sensitivity and 92% specificity in predicting staging increases. CONCLUSIONS: TE accurately predicts fibrosis progression in LT patients with recurrent hepatitis C, suggesting that protocol LB might be avoided in patients with improved or stable TE values during follow-up.

Increased expression of vascular endothelial growth factor in small hepatocellular carcinoma.

Vascular endothelial growth factor (VEGF) is involved in both development and progression of several epithelial tumours, but its role in hepatocellular carcinoma (HCC) is unclear. Assessment of liver and blood levels of VEGF may provide further insights on angiogenesis in HCC. Tissue mRNA of VEGF-165, VEGF-189 and their receptor KDR was assessed by a semi-quantitative retro-transcriptase polymerase chain reaction, and expressed as target transcript/beta-actin ratio, in 29 patients with HCC, 26 with cirrhosis and 15 with chronic hepatitis. VEGF-165 was also measured by ELISA in plasma samples obtained from both hepatic and femoral veins in additional 58 patients, including 15 with HCC. The liver expression of mRNA of VEGF-165, VEGF-189 and KDR was higher in HCC than in chronic liver diseases (1.54 +/- 0.89 vs 0.62 +/- 0.47, P < 0.0001; 1.09 +/- 0.65 vs 0.64 +/- 0.54, P = 0.003; 1.30 +/- 1.09 vs 0.69 +/- 0.72, P = 0.014). VEGF-165 was higher in HCC tissue than in extra-tumoural tissues (1.44 +/- 0.31 vs 1.03 +/- 0.21, P = 0.0009) and in the cirrhotic tissue of HCC patients than in HCC-free cirrhosis (1.03 +/- 0.23 vs 0.45 +/- 0.45, P = 0.0002). Tissue VEGF-189 mRNA inversely correlated with tumour size and degree of tumour cell proliferation. The hepatic and femoral vein levels of VEGF-165 protein were significantly higher in HCC patients than in cirrhotic patients (66.7 +/- 57.1 vs 24.2 +/- 16.4 pg/mL, P = 0.0001 and 37.1 +/- 42.2 vs 13.5 +/- 9.6 pg/mL, P = 0.001). There was a gradient of VEGF-165 between hepatic and femoral veins in both HCC and cirrhosis. In conclusion, VEGF appears to be involved in the development of HCC and it could be a predictor of HCC development in patients with cirrhosis.

Interferon-alpha suppresses liver cell proliferation in patients with chronic hepatitis C virus infection.

SUMMARY: Interferon (IFN) therapy has been shown to reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C, including virological nonresponders (NR). Whether IFN suppresses liver cell proliferation, i.e. the relevant risk factor for HCC, is unknown. The aim of the study was to evaluate the effect of IFN therapy on liver cell proliferation in chronic hepatitis C. The proliferating cell nuclear antigen-labelling index (PCNA-LI) was assessed prior to and at the end of therapy in the liver of 29 patients with chronic hepatitis C who received 3 MU IFN-alpha2b thrice weekly for 24-48 weeks. Overall, the median value of PCNA-LI was significantly reduced from 2.6% to 1.1% at the end of therapy (P < 0.0001). At baseline, PCNA-LI median values were similar in the 15 virological responders compared with the 14 NRs (2.3%vs 3.4%, P = 0.121) and at the end of therapy, median changes of PCNA-LI (-1.4%vs-1.1%, P = 0.089) were also similar although there was a higher decline of the proliferation index in responders with respect to NRs at the end of therapy (0.7%vs 1.6%, P = 0.004). In the two groups, the rate of fibrosis score reduction was also similar (7%vs 20%, P = 0.326). In contrast, the histological activity index was more often reduced in responders than in NRs both at the >or=2 and >or=4 points reduction level (80%vs 36%, P = 0.02 and 53%vs 14%, P = 0.03, respectively). The study showed a significant suppression of liver cell proliferation in IFN-treated patients with chronic hepatitis C. Although the strongest IFN effect was observed in virological responders, a reduction of proliferative activity was also seen in virological NRs.

Hepatitis C reactivation in patients with chronic infection with genotypes 1b and 2c: a retrospective cohort study of 206 untreated patients.

BACKGROUND: We previously described hepatitis reactivation in two carriers of the hepatitis C virus (HCV) genotype 2c. AIM: To assess the relationship between HCV genotypes and risk of hepatitis reactivation, we studied the course of aminotransferases in patients infected with the two relevant genotypes in Italy. PATIENTS: A cohort of 100 patients with genotype 2c chronic hepatitis and 106 with genotype 1b were subjected to surveillance. METHODS: Hepatitis reactivation was defined as an alanine aminotransferase (ALT) value > or =400 IU/l or a maximum/minimum ALT ratio value of > or =8. RESULTS: Over a period of 71 (24-144) months, one or more flares of ALT (201-2200 IU/l, 6-90 months' duration) occurred in 31 patients with genotype 2c and in eight patients with genotype 1b (rates of flares: 55.6 per 1000 person years for genotype 2c v 15.0 for genotype 1b; p=0.001). On repeat biopsy, hepatic fibrosis increased by more than 2 points in 10/16 patients examined either during or after an ALT flare compared with 7/36 flare free patients (63% v 19%; p=0.003). Hepatitis flares were significantly associated with genotype 2c (odds ratio 6.48 (95% confidence interval 2.57-16.35)) but not with sex, age, modality or duration of infection, baseline ALT values or histological severity of hepatitis, hepatitis other than HCV, or reinfection. CONCLUSIONS: Genotype 2c carriers are at high risk of hepatitis reactivation, suggesting that virus genetic heterogeneity is important in the natural history of HCV, questioning the linearity of hepatic fibrosis progression during hepatitis C.

High rate of positive anti-tissue transglutaminase antibodies in chronic liver disease. Role of liver decompensation and of the antigen source.

BACKGROUND: Since the recognition of tissue transglutaminase (tTG) as the target antigen of anti-endomysium antibodies, several ELISA assays using either guinea pig or human recombinant tTG have been developed. The aim of the study was to compare the behaviour of anti-tTG and anti-endomysium antibodies assays in coeliacs and in patients with chronic liver disease. METHODS: 34 patients (24 women, 34.9 +/- 12.5 years) with coeliac disease and 41 with chronic liver disease (14 women, 57 +/- 11.2 years), including 19 cirrhotics, were evaluated for anti-endomysium antibodies by indirect immunofluorescence and for anti-tTG IgA antibodies by ELISA, using guinea pig liver or human recombinant transglutaminase. RESULTS: The prevalences of anti-tTG and anti-endomysium antibodies were 100% in patients with coeliac disease at diagnosis, 75% and 64.3% in patients on a gluten-free diet. All liver disease patients were negative for anti-endomysium antibodies, while 11 (26.8%) were positive for anti-tTG. All these patients had liver cirrhosis and represented 57.9% of all cirrhotics. The presence of anti-tTG was associated with higher Child-Pugh scores. The use of human transglutaminase determined a reduction in the rate of positive results; however, the rate of positive anti-tTG was still 17.1% in all liver disease patients and 31.6% in cirrhotics. CONCLUSIONS: Our data confirm that anti-tTG have a similar sensitivity compared with anti-endomysium antibodies assay in coeliacs. However, a high prevalence of positive anti-tTG results is observed in cirrhotic patients, even when human recombinant tTG is used. The high prevalence of positive results among cirrhotic patients is associated with more advanced liver disease.

High Rate of Positive Anti-Tissue Transglutaminase Antibodies in Chronic Liver Disease.

BACKGROUND: Since the recognition of tissue transglutaminase (tTG) as the target antigen of anti-endomysium antibodies, several ELISA assays using either guinea pig or human recombinant tTG have been developed. The aim of the study was to compare the behaviour of anti-tTG and anti-endomysium antibodies assays in coeliacs and in patients with chronic liver disease. METHODS: 34 patients (24 women, 34.9 ± 12.5 years) with coeliac disease and 41 with chronic liver disease (14 women, 57 ± 11.2 years), including 19 cirrhotics, were evaluated for anti-endomysium antibodies by indirect immunofluorescence and for anti-tTG IgA antibodies by ELISA, using guinea pig liver or human recombinant transglutaminase. RESULTS: The prevalences of anti-tTG and anti-endomysium antibodies were 100% in patients with coeliac disease at diagnosis, 75% and 64.3% in patients on a gluten-free diet. All liver disease patients were negative for anti-endomysium antibodies, while 11 (26.8%) were positive for anti-tTG. All these patients had liver cirrhosis and represented 57.9% of all cirrhotics. The presence of anti-tTG was associated with higher Child-Pugh scores. The use of human transglutaminase determined a reduction in the rate of positive results; however, the rate of positive anti-tTG was still 17.1% in all liver disease patients and 31.6% in cirrhotics. CONCLUSIONS: Our data confirm that anti-tTG have a similar sensitivity compared with anti-endomysium antibodies assay in coeliacs. However, a high prevalence of positive anti-tTG results is observed in cirrhotic patients, even when human recombinant tTG is used. The high prevalence of positive results among cirrhotic patients is associated with more advanced liver disease.

Proliferating cell nuclear antigen assessed by a computer-assisted image analysis system in patients with chronic viral hepatitis and cirrhosis.

BACKGROUND: Assessment of liver cell proliferation by immunodetection of proliferating cell nuclear antigen may predict regenerative potential and survival of liver and hepatocellular carcinoma risk in patients with chronic viral hepatitis. AIM: To evaluate proliferating cell nuclear antigen status and its clinical significance in a large cohort of patients with chronic viral hepatitis and different degree of liver damage by a computer assisted imaging analysis system. MATERIALS: Liver biopsies from 358 patients with chronic hepatitis (259 males, 49 years, 63% with hepatitis C infection, 27% with hepatitis B virus, 10% with multiple infections) were studied. METHODS: Proliferating cell nuclear antigen was localised by immunoperoxidase on microwave oven pre-treated formalin-fixed, paraffin embedded sections using PC10 monoclonal antibody. Proliferating cell nuclear antigen labelling index was calculated by an automated imaging system (Immagini e Computers, Milan, Italy). RESULTS: Mean proliferating cell nuclear antigen labelling index ranged from 0.1% for patients with minimal changes to 3.6% for those with cirrhosis and hepatocellular carcinoma. Overall, proliferating cell nuclear antigen labelling index was higher in males, in older patients, in multiple infections and in hepatitis C virus compared to hepatitis B virus related cases. By linear regression analysis, proliferating cell nuclear antigen labelling index correlated with older age, male gender; higher transaminase levels, hepatitis C virus, higher histological gradIng and staging: by multivariate analysis male gender, hepatitis C virus, higher grading and staging resulted as independent variables. Both hepatitis C virus or hepatitis B virus cirrhotics had similar liver cell proliferation rate but those with hepatitis B virus had higher prevalence of liver cell dysplasia with respect to those with hepatitis C virus. CONCLUSIONS: Proliferating cell nuclear antigen labelling index was a reliable assay for assessing liver cell proliferation rate in patients with chronic viral hepatitis and correlated with liver disease severity

Progressive hepatic fibrosis in healthy carriers of hepatitis C virus with a transaminase breakthrough.

In short-term studies, patients with chronic hepatitis C virus (HCV) infection, consistently normal serum aminotransferase (ALT) levels, and minimal or mild necro-inflammatory changes in the liver, did not progress to histologically severe hepatitis. There are no data on longer term outcome of liver disease in these patients. We describe two patients with HCV infection (genotype 2c) with a rise in serum ALT values greater than 10 times the upper normal value that occurred after an 8- and 15-year period of persistently normal or minimally elevated ALT levels. In both patients, the rise in ALT values lasted more than 16 weeks and was not associated with any symptom or risk factor for acute hepatitis. A liver biopsy performed 4 and 18 months after the ALT flare showed clear-cut progression from chronic hepatitis with mild activity to chronic hepatitis with severe activity and central to portal septal fibrosis (Ishak score: grading 14 and 6; staging: 4 and 5, respectively). Hence, extended surveillance of HCV carriers with consistently normal or minimally elevated ALT values is warranted as these patients are at risk of ALT flares and may develop progressive liver disease.

High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity.

The prevalence, risk factors, and clinical significance of high liver cell proliferative activity were investigated in 208 well-compensated cirrhotic patients (150 men; 50 years; 135 with chronic hepatitis C) who had been under prospective surveillance for hepatocellular carcinoma (HCC) with annual abdominal ultrasound (US) and serum alpha-fetoprotein (AFP) determination. Immunostaining for proliferating cell nuclear antigen (PCNA) was employed to assess liver cell proliferative activity in formalin-fixed, paraffin-embedded liver specimens. The percentage of reactive nuclei was calculated by a computer-assisted image analysis system. The overall PCNA labeling index (LI) ranged from 0.1% to 12.5% (mean, 2.1%), being significantly higher in the 50 patients who developed HCC during 88 +/- 42 months of follow-up than in the 158 patients who remained cancer-free (3.6% +/- 2.4% vs. 1.6% +/- 1.5%; P <.0001). By receiver operating curve (ROC), a 2.0% cut-off value of PCNA-LI discriminated between patients at high and low risk for developing cancer. By multivariate analysis, high histologic grading scores and gender were associated to PCNA LI >2.0%. The yearly incidence of HCC was 5.2% for the 80 patients with PCNA-LI >2.0% compared with 1.1% for the 128 with low PCNA-LI (relative risk, 4.90; 95% CI, 2.63-9.55). By multivariate analysis, PCNA-LI >2.0% was the strongest independent predictor of cancer (hazard ratio, 5.49; 95% CI, 2.90-10.37). Overall, survival was significantly lower in patients with high liver cell proliferative activity rates than in those with low proliferative rates (10% vs. 75%; P <.0001). In conclusion, development of HCC in patients with compensated cirrhosis seems to be reliably predicted by liver cell proliferation status.

Sustained response to interferon-alpha2a monotherapy of young blood donors with minimal-to-mild chronic hepatitis C. The Donor Surveillance Study Group.

Subjects with minimal-to-mild chronic hepatitis C may suffer long-term consequences of hepatitis C virus (HCV) infection. Nonetheless, they are not candidates for antiviral treatment, mainly because little data are available concerning the efficacy and safety of therapy. Thirty-two HCV RNA positive individuals aged 18-45 years, who had a histological activity index score < or = 8 and alanine aminotransferase (ALT) levels < or = 1.5 times lower than the normal limit for at least 1 year, were prospectively enrolled among a cohort of 35358 candidate blood donors, and treated with 4.5 mega units (MU) of recombinant interferon-alpha2a (IFN-alpha2a) thrice weekly for 6 months, and for an additional 6 months if a virological response was observed. Twelve months after the completion of treatment, 13 of 31 evaluable patients were HCV RNA negative, accounting for a sustained response rate of 42%. Patients without fibrosis had a lower response rate than those with mild fibrosis (two of 14 vs 11 of 17; P=0.012). In responders, median aminotransferase levels were significantly lower after therapy than before (11.04 +/- 3.98 vs 27.3 +/- 12.32 U l-1, respectively; P < 0. 005). When the analysis was limited to the six responders whose pretreatment aminotransferase levels were consistently normal, this difference was still significant (9.33 +/- 4.12 vs 20.58 +/- 6.73 U l-1; P=0.002). In conclusion, a durable suppression of viraemia can be obtained by IFN monotherapy in a relatively high proportion of young subjects with minimal-to-mild chronic hepatitis C, especially when portal fibrosis is found on liver biopsy. The disappearance of viraemia always leads to a reduction in the degree of hepatocellular necrosis.

Hepatitis C is more severe in drug users with human immunodeficiency virus infection.

Drug users with chronic hepatitis C virus (HCV) infection are frequently co-infected with human immunodeficiency virus-1 (HIV-1), but it is still not clear whether HIV-1 worsens the natural history of hepatitis C. To investigate this, we conducted a multicentre observational study in 163 drug addicts with histologically documented hepatitis C, 92 of whom were also infected with HIV-1: 25 (27%) were CDC stage II, 53 (58%) were CDC stage III and 14 (15%) were CDC stage IV. Eighty-eight (54%) patients had chronic hepatitis (CH) with minimal activity, 28 (17%) had CH with moderate activity, 40 (25%) had CH with severe activity and seven (4%) had active cirrhosis. Twenty-one HIV-negative patients and 15 HIV-positive patients admitted to alcohol abuse (29% vs 16%, P=0.0665). Liver disease was more severe in HIV-positive patients than in HIV-negative ones (P=0.0198): 34 HIV-positive patients and 13 HIV negatives had severe CH and cirrhosis. These two severe liver diseases were seen more often in HIV-positive patients with a history of alcohol abuse than in HIV-negative patients (10 out of 16 vs seven out of 21). Age, alcohol abuse and distribution of the histological categories of liver disease were statistically different in HIV-infected and HIV-uninfected patients. Multivariate analysis showed that age, alcohol abuse and serum antibodies to HIV were independently associated with severe CH or cirrhosis. Thus, HIV may enhance the risk of severe liver disease in drug users with hepatitis C, independently of the degree of immune dysfunction. Alcohol abuse may contribute independently, aggravating the cause of HCV-dependent liver disease.

Transient oculomotor cranial nerves palsy in spontaneous intracranial hypotension.

Transient sixth cranial nerves palsy may occur in rare cases after lumbar puncture, spinal anesthesia and myelography as well as in more rare cases of spontaneous intracranial hypotension. We report three cases of spontaneous intracranial hypotension with sixth cranial nerves palsy. One of these patients presented also third cranial nerve palsy, never reported in spontaneous intracranial hypotension.

A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.

Short-term interferon treatment of serum hepatitis B e antigen (HBeAg)-negative carriers with serum hepatitis B virus (HBV) DNA and histological features of chronic hepatitis B has been largely unsuccessful. In a pilot study of long-term treatment, 42 such patients were randomly assigned to 6 million units of interferon alfa 2b (IFN-alpha2b) three times per week for 24 consecutive months (n = 21, 4 with cirrhosis) or to no therapy (n = 21, 3 with cirrhosis). Five patients (24%) discontinued therapy because of treatment-related adverse reactions. Serum levels of alanine transaminase (ALT) became persistently normal and HBV DNA undetectable by dot-blot assay in 8 patients receiving interferon and in 2 untreated controls (38% vs. 10%; P = .03). Hepatitis flare-ups disappeared in 17 patients during therapy compared with 6 controls (81% vs. 29%; P < .001). During a median period of 22 months after interferon was stopped, 2 treated patients (10%) lost serum hepatitis B surface antigen (HBsAg) and seroconverted to antibodies to hepatitis B surface antigen (anti-HBs). Serum ALT remained persistently normal and HBV DNA undetectable by dot-blot assay in 6 initial responders and 1 initial nonresponder, compared with none of the 21 untreated controls (sustained response: 33% vs. 0; P < .001). Comparative analysis of pre- and posttreatment liver biopsies showed that mean Knodell scores dropped in the treated group (10.3 to 5.3; P = .01), but not in the untreated group (9.3 to 9.8; not significant). In conclusion, a 24-month course of treatment with 6 MU IFN-alpha2b was well tolerated by most patients, led to sustained suppression of HBV in one third, and attenuated hepatitis in 81% of patients.

Immunological and endocrinological abnormalities in paraneoplastic disorders with involvement of the autonomic nervous system.

We report a series of four patients in whom the onset of systemic cancer was heralded by dysautonomic symptoms and a neurological non-metastatic complication mediated by immunological and endocrine factors. The series includes: a patient with acute leukaemia and autonomic sensory-motor polyradiculoneuropathy, a patient affected by colon carcinoma and autonomic neuropathy and limbic encephalitis, a patient with lung cancer and autonomic neuropathy and hypercalcaemic encephalopathy, a patient with small cell lung cancer associated with autonomic neuropathy in Lambert-Eaton Myasthenic Syndrome (LEMS) and syndrome of inappropriate ADH secretion (SIADH). We underline the prognostic importance and discuss the possible etiopathogenetic role of autonomic dysfunction, which is frequently associated with paraneoplastic neurologic syndromes of autoimmune and/or dysendocrine origin.