Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103/µl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.

Who is more likely to respond to dual treatment with pegylated-interferon and ribavirin for chronic hepatitis C? A gender-oriented analysis.

We assessed, in real-life practice, viral, demographic, genetic and metabolic factors influencing the sustained virologic response (SVR), with a gender-oriented analysis, in patients with chronic hepatitis C virus (HCV) treated with pegylated interferon and ribavirin. Six hundred and seventy naïve patients were treated with dual therapy and evaluated by gender and HCV genotype. Associations between baseline variables and SVR were assessed by multivariate logistic regression analysis. Among 362 genotype 1 patients, SVR was achieved in 158 patients (44%), and SVR was independently associated with age less than 50 years (OR 2.12; 95% CI 1.09-4.30; P=0.039) and C/C genotype rs12979860 SNP (OR 2.83; 1.19-6.74; P=0.002) in 163 females, while absence of visceral obesity (OR 2.491; 1.131-5.487; P=0.023), HCV-RNA lower than 400,000 IU/mL (OR 2.66; 1.273-5.558; P=0.009) and C/C genotype rs12979860 SNP (OR 4.969; 2.401-10.283; P<0.001) were independently associated with SVR in 199 males. Combining favourable baseline variables, the probability of obtaining SVR ranged from 27.6% to 84.2% in females, and from 14.3% to 85.7% in males. The rate of SVR was 81.1% in 175 genotype 2 patients, and 69% in 100 genotype 3 patients. Rapid virologic response was the only valid predictor of SVR regardless of other features. In conclusions, in the setting of HCV genotype 1, chronic hepatitis, combining rapid virologic response and predictive factors, which are different for females and males, allows clinicians to single out a group of patients whose likelihood of SVR exceeds 80%. For these patients, triple therapy with first-generation protease inhibitors may be unwarranted.

A 2010 update on occult hepatitis B infection.

Occult hepatitis B virus infection is a challenging issue whose virological and clinical relevance has been a source of long-lasting debate. By definition, OBI is characterized by the persistence of HBV-DNA in the liver tissue (and in some cases also in the serum) in absence of HBsAg. According to the HBV serological profile, OBI may be antibody (anti-HBc alone or together with anti-HBs) positive (seropositive OBI) or antibody negative (seronegative OBI). OBI is a complex biological entity with possible relevant clinical implications, mainly related to the intrahepatic persistence of viral cccDNA and to a strong suppression of viral replication and gene expression. Clinical observations suggest that OBI carriers may be a source of HBV transmission through blood transfusion or orthotopic liver transplantation (OLT). The state of suppression of viral replication and gene expression may be discontinued when an immunosuppressive status occurs, leading to typical hepatitis B with severe - and some times - fulminant course. The long-lasting persistence of the virus in the liver may provoke a very mild but continuing necro-inflammation that (if other causes of liver damage cohexist) may contribute over time to the progression of the chronic liver damage towards cirrhosis. In addition, OBI is supposed to be an important risk factor to HCC development since it maintains the pro-oncogenic properties typical of the overt infection.

An evaluation of transient elastography in the discrimination of HBeAg-negative disease from inactive hepatitis B carriers.

Liver biopsy is frequently required in HBeAg-negative disease to determine the stage of fibrosis. It can be difficult to distinguish cohorts with undetectable HBeAg who may have varying degrees of fibrosis due to different stages of disease. We have assessed the utility of transient elastography (TE) to evaluate differences in HBeAg-negative patients. A total of 220 HBsAg-positive individuals were studied: 125 (group 1) had an inactive HBsAg carrier state and 95 (group 2) were HBeAg-negative, anti-HBe-positive patients with persistently or intermittent elevation of alanine aminotransferase (ALT) and/or HBV DNA >10(5) copies/mL. Mean stiffness was 4.83 +/- 1.2 kPa in group 1 vs 8.53 +/- 6 kPa in group 2 (P < 0.001); statistically significant differences were also found between AST/ULN ALT/ULN ratios, HBV DNA in group 1 vs group 2, respectively (P < 0.001). In the multivariate analysis, the only variable independently associated with the stage of fibrosis was the stiffness. This study shows that mean hepatic stiffness by elastography is significantly lower in patients with inactive hepatitis B compared to those with HBeAg-negative disease. The procedure is a useful adjunct to diagnosis to confirm a clinical pattern of disease, and for more selective use of liver biopsy before considering antiviral therapy.

Menopause modulates homocysteine levels in diabetic and non-diabetic women.

High total homocysteine (tHcy) plasma levels may contribute to the increased cardiovascular risk of Type 2 diabetic women. However, to date, data on factors modulating tHcy concentration in this population are scarce. Fasting tHcy, vitamin B12, folate plasma levels, and the methylene tetrahydrofolate reductase (MTHFR) C677T genotype as well as clinical, biochemical, and lifestyle variables were compared in 91 Type 2 diabetic and 91 matched non-diabetic women (40 pre- and 51 post-menopausal, in each group). Fasting tHcy concentration did not differ between diabetic and control women, even after multivariable adjustment. In both groups, tHcy levels increased after menopause, but the differences were weakened after multivariable adjustment. The MTHFR genotype distribution was in accordance with the Hardy-Weinberg equilibrium, with a similar TT frequency in diabetic (22.2 %) and control women (19.8%). Overall, tHcy plasma concentration was higher in TT homozygous compared to other genotypes. We found a menopause-genotype interaction on tHcy levels (p=0.068 for menopause*genotype interaction); overall, the increase of tHcy concentration in TT subjects was limited to pre-menopause (p<0.0001; adjusted p=0.024), and this was confirmed after considering diabetic and control women separately (p=0.001 and p=0.01, respectively). At multivariate analysis, menopause was an independent correlate of tHcy concentration, together with creatinine, folate and MTHFR genotype. Our data show that menopause has a strong influence on tHcy concentration even in Type 2 diabetic women and demonstrate, for the first time, that it may modulate the association between tHcy and the common MTHFR polymorphism both in diabetic and non-diabetic women.

Is there a downgrading in the alert about the hepatitis B virus infection in Italy?

BACKGROUND AND AIM: There is suspicion of a decrease in warning regarding the hepatitis B virus as a health problem both by the infected individuals and their doctors. The aim of this study was to investigate whether the clinical/virology investigation of chronic hepatitis B virus infected individuals is at present accurate. METHODS: The chronic hepatitis B virus surface antigen carriers consecutively attending 13 different hospital divisions in Calabria from July to December 2005 were evaluated to investigate the available information on the grade of their liver disease, their virologic profile and the hepatitis B virus status of their family members. RESULTS: Four-hundred-thirty hepatitis B virus surface antigen positive individuals were enrolled, 417 of whom were Calabrians. Most of them had a diagnosis of chronic liver disease, but a liver biopsy had been performed only in 13.5% of the cases, whereas more than 1/3 of them had not been tested for hepatitis Delta virus co-infection. The majority of these individuals were unaware of the hepatitis B virus status of their family members. Moreover, anti-hepatitis B virus vaccination procedures were not performed in most of the hepatitis B virus surface antigen carrier families. CONCLUSIONS: This study revealed that fundamental clinical, virological, and epidemiological aspects of chronic hepatitis B virus infection are not investigated in many hepatitis B virus surface antigen carriers, suggesting that the general knowledge as regards hepatitis B virus is mostly inadequate.

Prophylaxis and treatment of hepatitis B in immunocompromised patients.

The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and referred mainly to the pre-antivirals era. Today a rational approach to the problem of hepatitis B in these patients provides for: (a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), (b) the treatment with antivirals (therapy) of active carriers, (c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if they are undergoing immunosuppressive therapies judged to be at high risk, (d) the biochemical and hepatitis B surface antigen (HBsAg) monitoring (or universal prophylaxis, in case of high risk immunosuppression) in subjects with markers of previous contact with HBV (HBsAg negative and anti-HBc positive), in order to prevent reverse seroconversion. Moreover it is suggested a strict adherence to criteria of allocation based on the virological characteristics of both recipients and donors in the general setting of transplants and in liver transplantation the universal prophylaxis with nucleos(t)ides analogues (frequently combined with specific anti-HBV immunoglobulins) in HBsAg positive candidates and in HBsAg negative recipients of anti-HBc positive grafts.

[Cognitive performances in workers with chronic virus hepatitis (HBV-HCV)]. / Performance cognitive in lavoratori affetti da epatite virale cronica (HBV-HCV).

Chronic condition in subjects with chronic viral hepatitis determines issues neuropsychic. The sample of 21 workers suffering from chronic viral hepatitis in drug treatment has been studied with a battery of standardized tests to assess the cognitive performance, the neurobehavioral effects and psychological disorders that interfere with quality of life, comparing the results of subjects with HBV with those of subjects suffering from HCV. The results showed that both subjects with chronic HBV and HCV have relational-work restrictions that determine long periods of absence from the workplace, with the depression, anxiety, irritability and dysphoria. It is that in patients with chronic HCV physical functioning is significantly impaired with clinical manifestations of the disease that lead to major depression and deficit cognitive function.

Does the margin width influence recurrence rate in liver surgery for hepatocellular carcinoma smaller than 5 cm?

OBJECTIVE: Liver surgery is considered a curative treatment for hepatocellular carcinoma (HCC) but the importance of resection margin width remains controversial. The aim of this study is to clarify the role of 5-10 mm surgical margin width on post-operative recurrence and overall survival after resection. PATIENTS AND METHODS: We analyzed recurrence rate and overall survival rate of 72 patients who underwent curative hepatic resection for HCC smaller than 5 cm with 5-10 mm surgical margin width between January 2005 and December 2014. RESULTS: The mean follow-up period was 36 months. Among the seventy-two patients, thirty-one (31/72; 43%) developed recurrence but only eleven (11/31; 15.3%) along the resection margin. The disease-free survival was 77.2%, 50%, 41.4% at 1, 3 and 5 years respectively, and the overall survival was 89.9%, 78.8%, 60% at 1, 3 and 5 years respectively. CONCLUSIONS: 5-10 mm surgical resection margin for HCC smaller than 5 cm seems to be safe as a wider surgical margin because does not increase the risk of marginal recurrence and does not decrease overall survival rate. Further prospective and randomized studies are required to definitively clarify the importance of surgical margin width in hepatic resection for HCC.

Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study.

BACKGROUND: Data on HCV-related hepatocellular carcinoma (HCC) early recurrence in patients whose HCC was previously cured, and subsequently treated by direct-acting antivirals (DAAs), are equivocal. AIM: To assess the risk of HCC early recurrence after DAAs exposure in a large prospective cohort of HCV-cirrhotic patients with previous successfully treated HCC, also looking for risk factors for cancer early recurrence. METHODS: We enrolled 143 consecutive patients with complete response after curative treatment of HCC, subsequently treated with DAAs and monitored by the web-based RESIST-HCV database. Clinical, biological, and virological data were collected. The primary endpoint was the probability of HCC early recurrence from DAA starting by Kaplan-Meier method. RESULTS: Eighty-six per cent of patients were in Child-Pugh class A and 76% of patients were BCLC A. Almost all patients (96%) achieved sustained virological response. Twenty-four HCC recurrences were observed, with nodular or infiltrative pattern in 83% and 17% of patients, respectively. The 6-, 12- and 18-month HCC recurrence rates were 12%, 26.6% and 29.1%, respectively. Main tumour size and history of prior HCC recurrence were independent risk factors for HCC recurrence by Cox multivariate model. CONCLUSIONS: Probability of HCC early recurrence in patients who had HCC previously cured remains high, despite HCV eradication by DAAs. Risk was comparable but not higher to that reported in literature in DAA-untreated patients. Previous HCC recurrence and tumour size can be used to stratify the risk of HCC early recurrence. Further studies are needed to assess impact of DAAs on late recurrence and mortality.

Neuropsychological outcome in long-term survivors of a childhood extracranial solid tumor who have undergone autologous bone marrow transplantation.

The purpose of this study was to evaluate neuropsychological and adaptive functioning of children who have undergone bone marrow transplantation (BMT) without previous cranial irradiation. In total, 76 children treated for an extracranial tumor with BMT without total body irradiation (TBI) were evaluated at least 5 years after the end of the treatment.Overall, their performance and skills were in the normal range and their professional and academic outcomes were satisfactory. Nevertheless, we observed a deleterious effect of deafness on verbal IQ associated with the previous administration of cisplatin during conventional chemotherapy. In addition, reading difficulties had arisen. This could be related to absence from kindergarten or primary school during hospitalization. Finally, in the younger subgroup, visual-perceptual skills were found to be more fragile.

Hepatitis B E antigen detection in formalin-fixed liver biopsy specimens. A tool to investigate wild-type and E-minus variant HBV infection.

The aim of this study is to investigate whether hepatitis B e antigen (HBeAg) reactivity can be detected on formalin-fixed, paraffin-embedded liver tissue, and whether immunohistochemical detection of intrahepatic HBeAg may help to distinguish between "wild-type" and "eminus" hepatitis B virus (HBV) infection. Liver biopsy specimens were analyzed from 27 patients with chronic type B hepatitis: 12 patients had serum HBeAg (group A), and 15 patients were anti-HBe positive (group B). Part of each biopsy fragment was processed for histologic and immunohistochemical studies, and a part was used for HBV-DNA analysis. Dewaxed sections from each specimen were tested with a specific monoclonal anti-HBe antibody; then a Biotin-Streptavidin kit was used as detection system. HBeAg was revealed in 10 of 12 cases of group A and in 6 of the 15 cases of group B. Pre-core region of HBV genomes, isolated from each biopsy specimen, was analyzed by direct sequencing: 10 cases of group A were found to be infected by wild-type HBV alone and 2 cases by both wild and e-minus HBV types. In group B, all the 6 cases with intrahepatic HBeAg reactivity were found to be infected by mixed viral population, whereas the 9 cases negative for such reactivity were found to be infected by e-minus HBV alone. These results show that HBeAg can be detected in formalin-fixed, paraffin-embedded liver specimens, and the method is sensitive and specific. Because the presence of HBeAg in the liver indicates a wild-type HBV infection, and the lack of detection of such antigen in the hepatocytes of anti-HBe positive subjects correlates with unmixed e-minus HBV infection, the authors conclude that this technique is a useful tool for recognizing the viral strains that infect patients with chronic type B hepatitis.

Immunohistochemical evidence of lactoferrin in hepatic biopsies of patients with viral or cryptogenetic chronic liver disease.

Lactoferrin (Lf) expression has been immunohistochemically investigated in 117 formalin-fixed paraffin-embedded liver bioptic samples obtained from an equal number of patients affected by chronic hepatitis (HCV = 76; HBV = 17; HBV + HDV = 14; cryptogenetic = 10); in addition, 10 autoptic specimens of normal liver were studied as control. The Lf immunoreactivity was evaluated by an intensity-distribution (ID) score. The Lf immunoexpression was observed in 88 out of 117 (75%) cases of chronic hepatitis; interestingly, all liver specimens from HBV hepatitis showed a constant Lf reactivity with the highest ID-score, whereas the evidence of Lf was encountered in 54/76 (71.1%) HCV as well as in 11/14 (78.6%) HDV chronic hepatitis, thus documenting a variable degree of Lf immunostaining in relation to different viruses. Moreover, in 6/10 (60%) cases of cryptogenetic hepatitis Lf immunoexpression was documented, whereas all normal liver controls were unreactive. In HCV specimens, the Lf nuclear immunoreactivity appeared to increase with the progression of the disease, with a greater expression in genotype 1. In contrast, no relationship among Lf ID-scores and different stages or grades of HBV, HDV or cryptogenetic hepatitis was encountered. This fact may suggest a role for Lf as an unspecific defensive agent in chronic inflammatory liver diseases, similarly to that elsewhere reported in other inflammatory tissue injuries.

Bile ductopenia following therapy with sulpiride.

We report a case of ductopenia associated with cholestatic hepatitis in a 59-year-old woman treated for 41 years for temporal epilepsy. The patient developed jaundice, without any clinical or biochemical features of hypersensitivity, 10 months after the beginning of treatment with sulpiride. Liver biopsy showed ballooning and acidophilic degeneration of the hepatocytes, macrophages packed with lipofuscin, biliary pigment in Kupffer cells, some biliary plugs, confluent necrosis and absence of biliary ducts in all the portal tracts. These features and the presence of foci of cholangiolitis suggest a destructive cholangitis as the pathogenetic mechanism causing ductopenia. Other causes of ductopenia were excluded. Sulpiride is known to produce severe cholestatic jaundice, which we believe is due to ductopenia. The absence of hypersensitivity and the 10-month latency suggest that sulpiride may cause liver damage through a toxic mechanism in genetically susceptible subjects.

Hepatitis B-DNA replication and histological patterns in liver biopsy specimens of chronic HBsAg positive patients with and without hepatitis delta virus superinfection.

The role of active hepatitis B virus (HBV) infection in chronic HBsAg positive hepatitis with and without hepatitis delta virus (HDV) superinfection was analysed in percutaneous liver biopsy specimens from 50 patients. Each specimen was divided into two--one part for histological evaluation and for the detection of HBcAg and delta antigen; the other part was tested for HBV-DNA using Southern blotting. Ten cases were of chronic lobular hepatitis, 10 of chronic persistent hepatitis, and 30 of chronic active hepatitis. Ten cases were delta antigen positive and showed high grade lobular activity but no evidence of HBV-DNA episomal forms or HBcAg reactivity. Twenty one cases showed HBV-DNA replicative intermediate forms; 19 had high grade lobular activity, which occurred in five cases without evidence of free viral DNA. Of the 21 biopsy specimens with HBV-DNA episomal forms, 14 were positive for HBcAg; only one of the 19 cases without detectable viral DNA was positive for such antigen. These data indicate that the presence of HBV or HDV active infection correlates with the histological finding of prominent lobular necrosis. Moreover, intrahepatic HBV-DNA seems to be a more sensitive marker than the presence of viral antigens for indicating HBV replication.

Histological behaviour of chronic hepatitis in patients treated with alpha interferon.

To evaluate the histological effects of alpha Interferon (IFN) therapy, serial liver biopsy specimens from 30 patients with chronic hepatitis were studied. The biopsies were examined using a scoring system. After 12 mths of IFN therapy responders were 8 out of 11 HBV infected patients, 10 out of 12 HCV infected patients and only 1 out of 7 patients with cryptogenetic hepatitis. As spontaneous improvement of hepatic changes is infrequent, our data indicate that in terms of histological patterns interferon therapy is effective in chronic viral hepatitis.

Occult hepatitis B virus infection.

Many studies have shown that hepatitis B virus infection may also occur in hepatitis B surface antigen-negative patients. This occult infection has been identified both in patients with cryptogenic liver disease and in patients with hepatitis C virus-related chronic hepatitis, and much evidence suggests that it may be a risk factor of hepatocellular carcinoma development. However several aspects of this occult infection remain unclear such as its prevalence and the factor(s) involved in the lack of circulating hepatitis B surface antigen. Moreover, it is uncertain whether the occult hepatitis B virus infection may contribute to chronic liver damage, considering that it is usually associated with a suppressed viral replication. Evidence and hypotheses concerning this fascinating field of bio-medical research are reviewed.

Occult HBV infection and suppression of HCV replication in the early phase of combination therapy for chronic hepatitis C.

BACKGROUND: Occult HBV infection in subjects with chronic hepatitis C is related to more severe disease outcome. It has been suggested that it might reduce sensitivity to antiviral treatment. AIMS: To assess in HBsAg negative subjects with chronic hepatitis C any effect of the presence of HBV genomes in the liver on the early kinetics of HCV-RNA under PEG-IFN plus ribavirin. PATIENTS AND METHODS: Twenty-two anti-HCV and HCV-RNA positive subjects, with biopsy-proven chronic hepatitis C (M/F 15/7; 50 +/- 8.6 years, 16 genotype 1b) were given PEG-IFN alpha 2b 1.0 microg qw plus ribavirin (800 to 1,200 mg daily according to body weight) for an intended 52 week period. Early virological response was assessed over the first 4 weeks of therapy by quantifying HCV-RNA. Occult HBV infection was assessed by testing for HBV-DNA in the liver before therapy. RESULTS: HBV genomes were found in the liver of 7 of 22 (31.4%) patients, unrelated to anti-HBc status. Kinetics of HCV-RNA during the first 4 weeks of antiviral treatment was unaffected by occult HBV infection, both in terms of absolute reduction of viral load and of number of cases with a reduction of > or = 2 log10 on treatment. CONCLUSIONS: Occult HBV infection does not affect the early phase of response to combination therapy. Further follow-up of patients into the maintenance phase of antiviral treatment and after stopping it will clarify if and when occult HBV has a role in reducing sustained virological response.

Apolipoprotein AI-CIII-AIV genetic polymorphisms and coronary heart disease in type 2 diabetes mellitus.

The aim of this study was to verify whether or not the increased prevalence of coronary heart disease (CHD) commonly observed in patients with type 2 diabetes mellitus is related to a genetic background involving restriction fragment length polymorphisms (RFLPs) of apolipoproteins. On the basis of a case-control design, 62 type 2 diabetic patients with CHD (confirmed by clinical history and electrocardiogram) and 62 age- and sex-matched diabetic subjects without CHD were enrolled. In each of them RFLPs of the apolipoprotein CIII gene (S1 or S2 allele) and AI promoter region (A or G allele), together with fasting plasma lipids and apolipoproteins levels, were assessed. The rare S2 allele was found significantly (P = 0.05) more frequently in patients with CHD, and its related S1S2 genotype was associated with higher plasma levels of total cholesterol (P = 0.01), triglycerides (P = 0.007) and apo B (P = 0.001) than the S1S1 genotype. The A allele was more frequent (P = 0.004) in patients without CHD and was associated with lower plasma cholesterol (P = 0.0001), low-density lipoprotein (LDL)-cholesterol (P = 0.0001) and apo B (P = 0.005). The S1/A haplotype was more frequent (P = 0.05) in patients without CHD and was associated with the lowest plasma lipid levels. These results suggest that genetic factors, related to the apo AI-CIII-AIV gene cluster, could play a role in the development of CHD in type 2 diabetic patients, probably through modification of their plasma lipid pattern.

Tauroursodeoxycholic acid for the treatment of HCV-related chronic hepatitis: a multicenter placebo-controlled study.

BACKGROUND/AIMS: Tauroursodeoxycholic acid is a promising drug for the treatment of chronic cholestatic liver diseases since it has more favourable physicochemical and metabolic properties than ursodeoxycholic acid. Tauroursodeoxycholic acid may be of benefit also for necroinflammatory liver disease, especially for HCV-related chronic hepatitis in which bile duct damage and some degree of cholestasis are frequently seen at histology. METHODOLOGY: One hundred and fifty patients with chronic hepatitis were randomly assigned to receive tauroursodeoxycholic acid at daily doses of 500 mg or 750 mg, or a placebo for 6 months. RESULTS: A consistent decrease in aminotransferase serum levels was observed in patients treated with tauroursodeoxycholic acid compared with placebo (p<0.001) and a progressive improvement with time was also found (p<0.05; linear time effect). CONCLUSIONS: Tauroursodeoxycholic acid improves the biochemical expression of chronic hepatitis. Long-term studies with clinically relevant end-points are warranted.