Substitution treatment or active intravenous drug use should not be contraindications for antiviral treatment in drug users with chronic hepatitis C.

INTRODUCTION AND AIMS: International guidelines and routine clinical practice express concerns about antiviral treatment in intravenous drug users (IDUs). We analysed the effect of IDU and/or substitution therapy on chronic hepatitis C (CHC) treatment adherence and response. PATIENTS AND METHODS: Intravenous drug users with CHC were divided into three groups: (A) patients on a substitution programme; (B) active users; and (C) past IDUs. Patients were treated according to the standard of care and followed by a specialist team. RESULTS: A total of 175 patients (mean age 39.4±8.8) were included. One hundred and forty-four (65%) were adherent to therapy (completing treatment and 6 months of follow-up). Twenty-two patients (36%) discontinued because of side effects, 28 (46%) discontinued on their own and 11 (18%) completed treatment but did not present at follow-up. Of 142 patients with available treatment outcome, 99 (69.7%) achieved a sustained virological response (SVR), with no differences among the study groups. Patients with genotypes 2-3 and those who completed the treatment schedule had 2.78-fold (95% CI: 1.3-5.8) and 6.4-fold (95% CI: 2.6-15.6) higher probability of achieving SVR. CONCLUSION: Active use of illicit drugs and/or drug substitution do not affect the treatment outcome in patients with CHC as long as they are closely followed and remain adherent to the treatment.

Pylephlebitis: an overview of non-cirrhotic cases and factors related to outcome.

Pylephlebitis is a condition with significant morbidity and mortality. We review herein 100 relevant case reports published since 1971. Eighty-one patients were reported with acute pylephlebitis, while the remaining patients had chronic pylephlebitis. The most common predisposing infections leading to pylephlebitis were diverticulitis and appendicitis. Cultures from blood or other tissues were positive in 77%. The infection was polymicrobial in half of the patients and the most common isolates were Bacteroides spp, Escherichia coli and Streptococcus spp. Thrombosis was extended to the superior mesenteric vein (SMV), splenic vein, and intrahepatic branches of the portal vein (PV) in 42%, 12%, and 39%, respectively. Antibiotics were administered in all and anticoagulation in 35 cases. Patients who received anticoagulation had a favourable outcome compared to those who received antibiotics alone (complete recanalization 25.7% vs 14.8% (p > 0.05), no recanalization 5.7% vs 22.2% (p < 0.05), and death 5.7% vs 22.2% (p < 0.01)). Cases with complete recanalization had prompt diagnosis and management and two-thirds were recently published. Nineteen patients died; the majority of these (73.7%) died over the period 1971-1990. In conclusion, pylephlebitis remains an entity with high morbidity and mortality, but modern imaging modalities have facilitated an earlier diagnosis and have improved the prognosis. Anticoagulation has a rather beneficial effect on patients with pylephlebitis.

Interferon alpha-induced hashimoto thyroiditis followed by transient graves disease in a patient with chronic HCV infection.

The case of a 37-year-old man with chronic hepatitis C virus (HCV) infection is presented. The patient had received a 6-month course of antiviral therapy with peg interferon alpha-2a and ribavirin, with concomitant clearance of hepatitis C virus ribonucleic acid (HCV-RNA) from serum at the end of treatment. Three months after the treatment course he developed clinical and laboratory features of hypothyroidism along with high titers of thyroid peroxidase antibodies. Later on, while on treatment with levothyroxine, he developed all the clinical features of Graves disease along with increased levels of thyroid stimulating hormone (TSH)-receptor antibodies.This patient exhibited a rare sequence of immune-mediated thyroid disorders as a result of interferon alpha treatment. At the end of treatment, the patient developed Hashimoto thyroiditis, a typically Th1-response-mediated disease, followed sequentially after 6 months by Graves disease, a typically Th2-response-mediated disorder. Although both clinical entities have been described in patients receiving interferon-based regimens, to our knowledge, the changing pattern of immune-mediated thyroid disease in the same individual has not been reported in the literature.

The burden of incidental findings in clinical practice in a tertiary care center.

BACKGROUND: To evaluate the prevalence and clinical burden of serendipitously discovered abnormalities in hospitalized patients, unrelated to their presenting symptoms and physical signs. METHODS: A total of 478 patients consecutively admitted in the Department of Medicine were enrolled in the study. In the end of first diagnostic work-up, the previously undetected imaging or endoscopic asymptomatic abnormalities termed as incidental findings (IFs) were recorded and some of them were further investigated. RESULTS: One hundred thirty eight (28.8%) patients had IFs. The most common IFs were located in the kidney and genitourinary system followed by liver and gallbladder. The most common method of detection of IFs was ultrasonography (US) of the abdomen. The patients with IFs compared with those without, were older (P=0.007), had no previous hospitalizations (P<0.001) and stayed longer in the hospital (P<0.001). The 25 (18.1%) patients with IFs were not evaluated further. One hundred seventy seven IFs discovered in 113 patients were further evaluated by medical specialists and additional tests were performed if warranted. In the end of the diagnostic work-up, in a total of 113 patients with IFs, 78.7% had insignificant and 21.2% potentially significant IFs. The latter group had higher rate of IFs compared with the former group, usually more than 3 (P=0.017). CONCLUSIONS: IFs were prevalent in a hospital population. Hospitalized patients with IFs were more than 60 years old and had no previous hospitalization. A large number of IFs were potentially significant deserving further clinical management.

Primary hepatic actinomycosis.

The clinical and imaging findings of primary hepatic actinomycosis are nonspecific and can mimic other diseases. This condition usually needs to be distinguished from other liver-occupying lesions, including malignancy. Review of the English language literature showed 67 cases of hepatic actinomycosis in immunocompetent, predominantly male patients. Infection was usually (75%) cryptogenic. The results of radiologic imaging showed that the lesion involved the right lobe in half of the cases, mimicked a liver tumor in 45%, and was single in two thirds of the cases. Hepatic actinomycosis coexisted with infections by common bacteria in 32% of cases reported. Diagnosis was usually achieved by microscopic examination of surgical or percutaneous specimens in 84.2% and 78.6%, respectively. Antibiotic therapy alone was used for treatment in approximately one half of cases and combined antibiotic treatment with surgical or percutaneous drainage procedure in the other half. The overall mortality rate was 7.6%. In conclusion, primary hepatic actinomycosis is a rare and usually cryptogenic infection. It is more common in men and immunocompetent subjects. It is well responsive to medical or combined medical and interventional treatment.

Serum apoptotic caspase activity in chronic hepatitis C and nonalcoholic Fatty liver disease.

BACKGROUND: Apoptotic caspases are substantially activated in liver and serum caspase activity has been suggested as a marker of early liver injury. AIM: To investigate whether serum levels of caspase-generated fragments of cytokeratin-18 are associated with the severity of histologic lesions in chronic hepatitis C virus (HCV) infection and nonalcoholic fatty liver disease (NAFLD). METHODS: We included 134 patients with chronic HCV infection and 58 patients with NAFLD, who consecutively underwent liver biopsy, and 40 healthy controls. Caspase-generated cytokeratin-18 fragment levels were blindly measured in stored serum samples. RESULTS: Median cytokeratin-18 fragment levels were lower in HCV-positive patients with minimal/mild than patients with moderate/severe histologic lesions (174 U/L vs. 223 U/L, P<0.001) offering moderate accuracy for differentiation between the 2 groups (c-statistic: 0.74). Cytokeratin-18 fragments levels were lower in healthy subjects (148 U/L) than patients with simple fatty liver (174 U/L, P=0.013) than patients with nonalcoholic steatohepatitis (355 U/L, P<0.001) offering excellent diagnostic accuracy for differentiation between the 2 latter groups (c-statistic: 0.87). CONCLUSIONS: Serum apoptotic caspase activity is associated with the severity of liver histologic lesions in both chronic HCV infection and NAFLD, but it has excellent diagnostic accuracy in NAFLD and moderate accuracy in chronic HCV patients.

The burden and recent epidemiological changes of the main chronic liver diseases in a Greek referral tertiary centre.

OBJECTIVE: To investigate the burden and recent epidemiological changes of the main chronic liver diseases in a Greek referral tertiary centre. METHODS: We evaluated the main epidemiological characteristics of 1080 consecutive adult patients, seen at our outpatient liver clinic between 2002 and 2007, with chronic hepatitis B (HBV) and/or C (HCV) virus infection, alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD). Our patient population was divided into two groups in relation to the time of the first visit (period A: 2002-2004, period B: 2005-2007). RESULTS: Among our patient population, 86.1% had chronic HBV and/or HCV infection (chronic HCV alone: 44.9%), 9.2% NAFLD and 4.8% ALD. From period A to B, there was a decrease in chronic HBV cases (44.0 vs. 37.8%, P = 0.045) with immigrants being responsible for 35.5% of them and being more frequent in period B than A (39.7 vs. 30.5%, P = 0.046). In chronic hepatitis B, hepatitis B e antigen-positive patients, who were more frequent immigrants compared with hepatitis B e antigen-negative patients (65.5 vs. 29.5%, P = 0.001), increased from period A to B (8.0 vs. 17.6%, P = 0.045). Intravenous drug use was reported by 41.2% of HCV patients with its proportion increasing from period A to B (32.5 vs. 47.4%, P = 0.002). Decompensated cirrhosis was present in 67, 10, 11 and 3% of patients with ALD, HBV, HCV and NAFLD, respectively. CONCLUSION: At Greek tertiary centres, chronic viral hepatitis remains responsible for most chronic liver disease cases, but its epidemiology is changing owing to immigrants and intravenous drug users.

Thrombotic risk factors and liver histologic lesions in non-alcoholic fatty liver disease.

BACKGROUND/AIMS: The pathogenetic mechanisms of development of non-alcoholic steatohepatitis (NASH) and fibrosis are not clear, although thrombosis of small intrahepatic veins has been suggested to trigger liver tissue remodelling and thrombotic risk factors have been associated with more advanced fibrosis in chronic viral hepatitis (CVH). We evaluated the prevalence of thrombotic risk factors (RFs) in non-alcoholic fatty liver disease (NAFLD) and their possible association with fatty liver or NASH. METHODS: We included 60 patients with histologically documented NAFLD and a historical cohort of 90 patients with chronic hepatitis B (n=39) or C (n=51). Thrombophilic factors were evaluated on the day of the liver biopsy. RESULTS: One or more thrombotic RFs were detected in 37% of NAFLD patients, and >or= 2 RFs were detected in 12% of NAFLD patients, being less frequently present than in CVH patients (37% and 68%, respectively; P

Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and can vary from benign steatosis to end-stage liver disease. The pathogenesis of non-alcoholic steatohepatitis (NASH) is currently thought to involve a multiple-hit process with the first hit being the accumulation of liver fat which is followed by the development of necroinflammation and fibrosis. There is mounting evidence that cytokines secreted from adipose tissue, namely, adipokines, are implicated in the pathogenesis and progression of NAFLD. In the current review, we explore the role of these adipokines, particularly leptin, adiponectin, resistin, tumor necrosis factor-a, and interleukin-6 in NASH, as elucidated in experimental models and clinical practice. We also comment on their potential use as noninvasive markers for differentiating simple fatty liver from NASH as well as on their potential future therapeutic role in patients with NASH.

Current management of hepatitis B virus infection before and after liver transplantation.

The progress in treatment against hepatitis B virus (HBV) has substantially improved the outcome of all HBV-infected patients. We systematically reviewed the existing data in the management of HBV transplant patients in order to assess the optimal regimen in the pretransplant setting, for post-transplant prophylaxis and for therapy of HBV recurrent infection. All data suggest that an effective pretransplant anti-HBV therapy prevents post-transplant HBV recurrence. Pretransplant therapy has been based on lamivudine with addition of adefovir upon lamivudine resistance, but the use of newer, potent high-genetic barrier agents is expected to improve long-term efficacy. Moreover, it may lead to improvement of liver function, which sometimes removes the need for transplantation, although more objective criteria for removal from waiting lists are required. After liver transplantation, the combination of HBV immunoglobulin and one nucleos(t)ide analogue, mostly lamivudine, is currently the best approach, almost eliminating the probability of HBV recurrence. Treatment of post-transplant HBV recurrence has been mainly studied with lamivudine, but it will be most effective with entecavir and tenofovir, which have a low risk of resistance. In conclusion, the newer anti-HBV agents improve the treatment of HBV both pretransplant and post-transplant. HBV immunoglobulin is still used in combination with an anti-HBV agent for post-transplant prophylaxis. Monoprophylaxis with one of the new anti-HBV agents might be possible, particularly in patients preselected as having a low risk of HBV recurrence, but further data are needed and strategies to ensure compliance must be used.

Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B.

OBJECTIVE: The results of retrospective studies suggest an association between smoking, insulin resistance, steatosis and fibrosis in patients with chronic hepatitis C (CHC); no data are available for chronic hepatitis B (CHB). The purpose of this study was to evaluate the relationship, if any, of such factors on liver fibrosis in a cohort of patients with CHB and CHC. MATERIAL AND METHODS: The study prospectively included 271 consecutive patients with CHB (n=95) or CHC (n=176) who had undergone liver biopsies. Each patient completed a questionnaire on smoking habits; anthropometric measurements and laboratory examinations were carried out and histological lesions were recorded. RESULTS: In CHC patients, severe fibrosis was independently associated with a higher body mass index (BMI) (OR: 1.180, 95% CI: 1.028-1.354; p=0.019), heavy smoking (OR: 3.923, 95% CI: 1.356-11.348; p=0.012), higher alanine aminotransferase (ALAT) levels (OR: 1.010, 95% CI: 1.003-1.017; p=0.005) and alkaline phosphatase (ALP) levels (OR: 1.016, 95% CI: 1.001-1.030; p=0.03) and presence of necroinflammation (OR: 11.165, 95% CI: 1.286-96.970; p=0.029). Moreover, steatosis was independently associated with high gamma-glutamyl transpeptidase (GGT) values, heavy smoking and presence of necroinflammation. In CHB patients, no association between smoking habits and fibrosis or steatosis was noted. CONCLUSIONS: Heavy smoking is associated with severe fibrosis in CHC but not CHB. Heavy smoking is also significantly associated with steatosis in CHC and this could be the link between smoking and fibrosis progression.

Core mutations in patients with acute episodes of chronic HBV infection are associated with the emergence of new immune recognition sites and the development of high IgM anti-HBc index values.

Acute exacerbations in HBeAg negative patients with chronic hepatitis B virus (HBV) infection are invariably associated with concurrent increases in the index of IgM class antibodies against the core protein (anti-HBc) of the virus. This study aimed to investigate whether this was related to the clearance of variants from the quasispecies pool and the appearance of new ones, with aminoacid substitutions in well recognized B-cell epitopes. In this study, 5 HBeAg negative patients (A to E) with 13 sequential serum samples (A1-A2, B1-B2-B3, C1-C2, D1-D2-D3, E1-E2-E3) were investigated after amplification of the entire core encoding region followed by cloning/sequencing studies. The sequences at different time points were compared with those from a single HBeAg positive patient with no apparent acute exacerbations. The results from sequence comparison showed that virus variants emerged in all (A2, B3, C2, D3, E2, and E3) but two (B2 and D2) subsequent sera with amino-acid substitutions affecting B-cell epitopes. It is concluded that the rise in the values of IgM anti-HBc may be attributed to the alteration of the antigenic epitopes leading to new antibody production in the majority of the cases. However, it appears that increases in IgM anti-HBc indexes in a few cases may relate to other possible mechanisms which are discussed.

Insulin resistance and metabolic syndrome in chronic liver diseases: old entities with new implications.

Insulin resistance (IR) and metabolic syndrome have recently been implicated in the pathogenesis and progression of chronic liver diseases, especially chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). In this review, we provide current information on their deleterious effect on the liver, with particular interest in those two entities. In NAFLD, IR causes both the accumulation of fat in hepatocytes and the progression to non-alcoholic steatohepatitis (NASH). Moreover, the presence of metabolic syndrome seems to be associated with severe fibrosis in NASH patients. In CHC, IR develops early in the course of the disease and precedes steatosis. It is also independently associated with histological severity and negatively affects treatment response, irrespective of genotype. Consequently, therapies targeting IR and metabolic syndrome could indirectly ameliorate the prognosis of both NAFLD and CHC. As specific therapies do not exist, patients with metabolic syndrome and CHC and NAFLD should be counseled to lose weight and ameliorate their glycemic control and lipid profile.

Unusual combination of paraneoplastic manifestations in a patient with metastatic gastrointestinal stromal tumor (GIST).

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Activating mutations in tyrosine kinase receptors KIT or platelet-derived growth factor receptor alpha (PDGFRA) are the main mechanisms causing the disease. Patients generally present with non-specific symptoms, while a number of tumors are discovered incidentally and may be metastatic at the time of diagnosis. Aggressive GISTs have a defined pattern of metastasis to the liver or throughout the abdomen, or both. Though GISTs rarely present systemic or isolated paraneoplastic reactions, a few cases have been reported in the literature. We present the case of a 54-year-old patient with metastatic GIST at diagnosis and the emergence of paraneoplastic manifestations during follow-up.

Current treatment indications and strategies in chronic hepatitis B virus infection.

The optimal approach to the management of several marginal cases with chronic hepatitis B virus (HBV) infection is controversial. Serum HBV DNA and aminotransferase levels, and the degree of necroinflammation and fibrosis determine the therapeutic decisions. All patients with elevated aminotransferase (>twice the upper limit of normal) and serum HBV DNA above 20000 IU/mL should be treated. Liver biopsy is important for therapeutic decisions in cases with mild aminotransferase elevations and serum HBV DNA below 20000 IU/mL. Chronic HBV patients who do not receive treatment should be followed for life. There are seven agents licensed for chronic hepatitis B: standard and pegylated interferon-alpha, lamivudine, adefovir, entecavir, telbivudine and tenofovir. One-year courses with pegylated interferon-alpha induce sustained off-therapy remission in 30%-32% of patients with HBeAg-positive chronic hepatitis B and in a smaller proportion of patients with HBeAg-negative chronic hepatitis B. Oral antivirals achieve initial on-therapy responses in the majority of patients, but are intended as long-term therapies. Viral suppression has favourable effects on patients' outcome and modifies the natural course of the disease. Viral resistance, however, is the major drawback of long-term oral antiviral therapy. Lamivudine monotherapy is associated with the highest and entecavir monotherapy with the lowest resistance rate so far. There has been no resistance to tenofovir, but after only 18 mo of treatment to date. The optimal first-line anti-HBV therapy with the best long-term cost/benefit ratio remains unclear. If oral antiviral agents are used, compliance should always be ascertained and HBV DNA levels should be regularly tested.

Adverse drug reactions as a cause of hospital admissions: a 6-month experience in a single center in Greece.

BACKGROUND: Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. METHODS: A prospective study was conducted over a 6-month period. All patients consecutively admitted were enrolled in the study. Analysis included: (1) an evaluation of the frequency of ADR-related hospital admissions and their causality, severity, and preventability; (2) a description of the type of drugs involved; (3) a report of the most common clinical manifestations related to these ADRs; and (4) an assessment of the factors that were predictive of ADRs. RESULTS: Seventy of the 548 admissions (12.8%) were related to an ADR. Hemorrhage represented the most common ADR (37.3%), followed by metabolic and renal events (10.8% each). The drugs most often involved were non-steroid anti-inflammatory drugs (NSAIDs), followed by diuretics, aspirin, oral anticoagulants, and oral hypoglycemic agents. A comparison between ADR and non-ADR-related admissions showed that mean number of medications and age were significantly higher for patients admitted for an ADR than for those who were not. Gender, chronic disease at admission, days of hospitalization, cognitive impairment, renal insufficiency, physical activity impairment, and use of psychoactive drugs did not differ between the two groups. In the multivariate analysis, number of drugs was the only independent predictor of ADR-related hospital admission (OR=1.064, 95% CI 1.019-1.109). In 13 of 70 (18.6%) ADR-related hospital admissions, ADRs were coded as severe. CONCLUSIONS: ADRs are common causes of hospital admissions and may have important consequences. The most important determinant for ADR-related hospital admissions is the number of drugs taken.

Cholangiocarcinoma: a 7-year experience at a single center in Greece.

AIM: To evaluate survival rate and clinical outcome of cholangiocarcinoma. METHODS: The medical records of 34 patients with cholangiocarcinoma, seen at a single hospital between the years 1999-2006, were retrospectively reviewed. RESULTS: Thirty-four patients with a median age of 75 years were included. Seventeen (50%) had painless jaundice at presentation. Sixteen (47.1%) were perihilar, 15 (44.1%) extrahepatic and three (8.8%) intrahepatic. Endoscopic retrograde cholangiography (ERCP) and/or magnetic resonance cholangiography (MRCP) were used for the diagnosis. Pathologic confirmation was obtained in seven and positive cytological examination in three. Thirteen patients had co-morbidities (38.2%). Four cases were managed with complete surgical resection. All the rest of the cases (30) were characterized as non-resectable due to advanced stage of the disease. Palliative biliary drainage was performed in 26/30 (86.6%). The mean follow-up was 32 mo (95% CI, 20-43 mo). Overall median survival was 8.7 mo (95% CI, 2-16 mo). The probability of 1-year, 2-year and 3-year survival was 46%, 20% and 7%, respectively. The survival was slightly longer in patients who underwent resection compared to those who did not, but this difference failed to reach statistical significance. Patients who underwent biliary drainage had an advantage in survival compared to those who did not (probability of survival 53% vs 0% at 1 year, respectively, P = 0.038). CONCLUSION: Patients with cholangiocarcinoma were usually elderly with co-morbidities and/or advanced disease at presentation. Even though a slight amelioration in survival with palliative biliary drainage was observed, patients had dismal outcome without resection of the tumor.

Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B virus infection?

UNLABELLED: The diagnosis of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B indicating therapeutic intervention currently requires serum hepatitis B virus (HBV) DNA >or=2,000 IU/mL. We evaluated the severity of liver histology and the presence of histological indication for treatment in patients with HBeAg-negative chronic HBV infection focusing on those with low viremia and/or normal alanine aminotransferase (ALT). In total, 399 patients with increased ALT and detectable serum HBV DNA (chronic hepatitis B patients) and 35 cases with persistently normal ALT and HBV DNA >2,000 IU/mL (inactive carriers) were included. Histological indication for treatment (grading score >or=7 and/or stage >or=2 in Ishak's classification) was found in 91% (185/203), 82% (75/91), 75% (47/63), and 62% (26/42) of chronic hepatitis B patients with HBV DNA >or=200,000, 20,000-199,999, 2,000-19,999, and <2,000 IU/mL, respectively (P < 0.001). Histological indication for treatment was more frequent in chronic hepatitis B patients with persistently elevated ALT (86% or 275/321), but it was also found in 74% (58/78) of those with transiently normal ALT (P = 0.025). All inactive carriers had HBV DNA <20,000 IU/mL. Histological indication for treatment was present in 17% (6/35) of inactive carriers always due to moderate (stage 2) fibrosis without active necroinflammation. CONCLUSION: HBeAg-negative chronic HBV patients with persistently or transiently increased ALT and HBV DNA >or=20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such cases with HBV DNA <20,000 and even <2,000 IU/mL. In contrast, minimal histological lesions are observed in the majority of HBeAg-negative patients with persistently normal ALT and HBV DNA >2,000 IU/mL, who may not require immediate liver biopsy and treatment but only close follow-up.