Serum HBsAg kinetics and usefulness of interferon-inducible protein 10 serum in HBeAg-negative chronic hepatitis B patients treated with tenofovir disoproxil fumarate.

The kinetics of serum HBsAg and interferon-inducible protein 10 (IP10) levels in patients with chronic hepatitis B infection treated with tenofovir are unclear. We evaluated the changes of HBsAg levels and the predictability of IP10 for HBsAg decline in 160 HBeAg-negative patients receiving tenofovir for ≥12 months. Serum samples taken before and at 6, 12, 24, 36 and 48 months after tenofovir were tested for HBsAg levels. In 104 patients, serum samples before tenofovir were tested for IP10 levels. Compared to before tenofovir, HBsAg levels decreased by a median of 0.08, 0.11, 0.24, 0.33 and 0.38 log10 IU/mL at 6, 12, 24, 36 and 48 months, respectively (P < 0.001). HBsAg kinetics did not differ between nucleos(t)ide analogue(s) naive and experienced patients. The 12-, 24-, 36- and 48-month cumulative rates of ≥0.5 log10 HBsAg decline were 8%, 16%, 24% and 41% and of HBsAg ≤100 IU/mL were 9%, 12%, 14% and 18%, respectively. The only factor associated with HBsAg ≤100 IU/mL was lower HBsAg levels before tenofovir (P < 0.001), while HBsAg decline ≥0.5 log10 was associated with higher IP10 levels (P = 0.002) and particularly with IP10 > 350 pg/mL (P < 0.001). In conclusion, tenofovir decreases serum HBsAg levels in both nucleos(t)ide analogue(s) naive and experienced patients with HBeAg-negative chronic hepatitis B infection. After 4 years of therapy, HBsAg ≤100 IU/mL can be achieved in approximately 20% of patients, particularly in those with low baseline HBsAg levels. HBsAg decline is slow (≥0.5 log10 in 40% of patients after 4 years) and is associated only with higher baseline serum IP10 levels.

Cirrhosis but not neutropenia is associated with the development of infection in patients with chronic hepatitis C undergoing treatment with pegylated interferon-alpha and ribavirin.

Peginterferon-alpha (PegIFNa) frequently causes neutropenia, mainly due to bone marrow suppression. The aim of this study was to explore factors that are associated with infections during antiviral treatment. We analysed data from 275 chronic hepatitis C (CHC) patients with compensated liver disease who underwent 318 courses of PegIFNa and ribavirin. Neutropenia was defined as neutrophils <1000 cells/µL. Mean leucocytes count significantly decreased from baseline to treatment nadir (7081 ± 2182 vs 3293 ± 1331 cells/µL, P < 0.001), while neutropenia was observed in 32% during treatment. Thirty-one infections were observed. The incidence rate for infection was assessed at 1.46 infections per 100 person-months of therapy. The hazard rate for infection did not correlate with the neutrophils' nadir or the decrease in white blood cells. In multivariate Cox's regression analysis, cirrhosis was the only factor that was significantly associated with the occurrence of infection. Our data show that the development of bacterial infections during treatment with PegIFNa and ribavirin in patients with compensated CHC is not associated with reduction or the nadir of white cells or neutrophil counts. Baseline cirrhosis is the only factor related with infection during treatment. The common practice of dose adjustment or discontinuation of interferon should be revised; careful assessment of liver damage before therapy and close monitoring during therapy are essential in all patients receiving interferon-based regimes, to minimize the detrimental consequences of infections.

Non-variceal gastrointestinal bleeding in patients with liver cirrhosis: a review.

BACKGROUND: Non-variceal gastrointestinal (NVGI) bleeding in cirrhosis may be associated with life-threatening complications similar to variceal bleeding. AIM: To review NVGI bleeding in cirrhosis. METHODS: MEDLINE, Scopus, and ISI Web of Knowledge were searched, using the textwords "portal hypertensive gastropathy," "gastric vascular ectasia," "peptic ulcer," "Dieulafoy's," "Mallory-Weiss syndrome," "portal hypertensive enteropathy," "portal hypertensive colopathy," "hemorrhoids," and "cirrhosis." RESULTS: Portal hypertensive gastropathy (PHG) and gastric vascular ectasia (GVE) are gastric lesions that most commonly present as chronic anemia; acute upper GI (UGI) bleeding is a rare manifestation. Management of PHG-related bleeding is mainly pharmacological, whereas endoscopic intervention is favored in GVE-related bleeding. Shunt therapies or more invasive techniques are restricted in refractory cases. Despite its high incidence in cirrhotic patients, peptic ulcer accounts for a relatively small proportion of UGI bleeding in this patient population. However, in contrary to general population, the pathogenetic role of Helicobacter pylori infection remains questionable. Finally, other causes of UGI bleeding include Dieulafoy's lesion, Mallory-Weiss syndrome, and portal hypertensive enteropathy. The most common non-variceal endoscopic findings reported in patients with lower gastrointestinal bleeding are portal hypertensive colopathy and hemorrhoids. However, the vast majority of studies are case reports and, therefore, the incidence, diagnosis, and risk of bleeding remain undefined. Endoscopic interventions, shunting procedures, and surgical techniques have been described in this setting. CONCLUSIONS: The data on NVGI bleeding in liver cirrhosis are surprisingly scanty. Large, multicenter epidemiological studies are needed to better assess prevalence and incidence and, most importantly, randomized studies should be performed to evaluate the success rates of therapeutic algorithms.

Meta-analysis: antiviral treatment for hepatitis D.

BACKGROUND: There is no satisfactory treatment for patients with hepatitis D (HDV). AIM: To evaluate treatment for HDV using meta-analysis. METHODS: Medline, Scopus, Cochrane Library and ISI Web of Knowledge searches using the textwords 'Hepatitis D', 'therapy', "interferon", "peginterferon", "pegylated interferon", "lamivudine", "pegifn", "ifn" and "Hepatitis D", and abstracts from major Gastroenterology/Liver meetings. ENDPOINTS: end of treatment biochemical (biochemical EOT) and virological response (virological EOT), end of follow-up virological response (EOFUP VR), histological improvement and intrahepatic HDAg clearance. RESULTS: We included randomised clinical trials (RCTs) comparing Group A: interferon-A (IFNa) vs. no treatment (three RCTs, n ;= ;137 patients), Group B: low dose vs. high dose IFNa (two RCTs, n ;= ;60), Group C: IFNa ;+ ;lamivudine vs. IFNa (two RCTs, n ;= ;48) and Group D: pegylated IFNa (PEG-IFNa) vs. other medications (two RCTs, n ;= ;157). Group A. IFNa was better for biochemical EOT [OR, 0.11 (95% CI, 0.04-0.2)] and virological EOT [OR, 0.08 (95% CI, 0.03-0.2)], but not for EOFUP VR. Group B. High dose IFNa was better for biochemical EOT [OR, 0.24 (95% CI,0.08-0.73)] and virological EOT [OR, 0.27 (95% CI, 0.1-0.74)]. Group C. There was a trend favouring histological improvement [OR, 2.9 (95% CI, 0.6-13.4)]. Group D. PEG-IFNa was better for virological EOT [OR, 0.419 (95% CI, 0.18-0.974)], EOFUP VR [OR, 0.404 (95% CI, 0.189-0.866)] and improvement in necroinflammatory activity [OR, 0.308 (95% CI, 0.129-0.732)]. CONCLUSIONS: Long-term suppression of HDV RNA by IFNa is not maintained despite an end of treatment response; adding lamivudine is not beneficial. PEG-IFNa is superior to other medications with respect to EOT and EOFUP. New RCTs should test combinations of PEG-IFNa and newest antivirals.

Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis.

BACKGROUND: There is no satisfactory medical treatment for patients with primary sclerosing cholangitis. There are conflicting data regarding the clinical benefit of high doses of ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis. AIM: To evaluate using meta-analysis, if UDCA (standard or high-dose) is useful in primary sclerosing cholangitis. METHODS: We searched MEDLINE using the textwords 'PSC', 'treatment', 'UDCA' and retrieved all abstracts from the major Gastroenterology and Liver meetings. We included randomised clinical trials comparing standard or high-dose of UDCA (>15 mg/kg body weight per day) vs. placebo or no intervention. End-points: mortality or liver transplantation, pruritus, fatigue, cholangiocarcinoma and histological progression. RESULTS: We identified eight randomised clinical trials comprising 567 patients. Five used standard doses and three high doses of UDCA. There was no significant difference in mortality [OR, 0.6 (95% CI, 0.4-1.4)], in pruritus [OR, 1.5 (95% CI, 0.3-7.2)], in fatigue [OR, 0.0 (95% CI, 0.1-7.7)], in cholangiocarcinoma [OR, 1.7 (95% CI, 0.6-5.1)] and in histology stage progression [OR, 0.9 (95% CI, 0.34-2.44)]. No differences were found in the subgroup analyses. CONCLUSION: Neither standard nor high-dose UDCA influence favourably the progression of primary sclerosing cholangitis.

Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study.

BACKGROUND: Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes. AIM: To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR. METHODS: We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5-6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006). CONCLUSIONS: IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.

Pegylated-interferon and ribavirin in liver transplant candidates and recipients with HCV cirrhosis: systematic review and meta-analysis of prospective controlled studies.

SUMMARY: Pegylated interferon with ribavirin (Peg/R) is the most effective therapy for chronic hepatitis C virus (HCV) but its utility and effectiveness after liver transplantation has been difficult to assess. We evaluated efficacy, tolerability, and safety of Peg/R in liver transplant candidates and recipients with HCV cirrhosis. We searched medical databases and conference proceedings between January 1999 and January 2008 selecting randomized and nonrandomized studies. Primary end points meta-analytically were: (1) sustained viral response (SVR) and (2) histological response. Secondary end points were: (1) treatment discontinuation, (2) mortality, and (3) rejection episodes. Pegylated interferons using either 1-1.5 mcg/kg of pegylated interferon alpha-2b or 180 microg (pegylated interferon alpha-2a combined with ribavirin 800-1200 mg/day were the most effective compared to any other regimen or no therapy. In three pretransplant studies the median SVR was 19.6% (19.6-50%). In six postransplant studies where a meta-analysis was done the cumulative risk difference in SVR was 0.31% (95% CI, 0.18-0.44, p < 0.001). However histological response was not significantly better compared to no therapy or other antiviral regimens. There were no significant differences in discontinuation of therapy, acute or chronic rejection or mortality between optimal Peg/R vs no treatment or other regimens. Hence pegylated interferon plus ribavirin in full doses is effective pre and post transplant but has a low SVR rate. To date no significant histological improvement has been reported.

Review article: the therapeutic and prognostic benefit of portal pressure reduction in cirrhosis.

BACKGROUND: Hepatic venous pressure gradient (HVPG) measurement is not a routinely used technique, despite its therapeutic and prognostic value. AIM: To review the role of HVPG from published literature. METHODS: Systematic literature review. RESULTS: In acute variceal bleeding, HVPG is prognostic identifying 'difficult to treat' group, which now has defined clinical correlations. In secondary prevention of portal hypertensive bleeding, a reduction to < or = 12 mmHg confers near complete protection against rebleeding. The target of > or = 20% HVPG reduction from baseline needs prospective assessment to test a change of therapy, if no reduction occurs. The acute HVPG response to beta-blockade needs further assessment. In primary prevention, the cost-effectiveness of HVPG measurement is not favourable given the efficacy of medical therapy. In chronic liver disease, wedge hepatic venous pressure (WHVP) is prognostic for survival. Pharmacological reduction in portal pressure decreases complications and improves survival, possibly independent of a concomitant improvement in liver function. This latter requires urgent confirmation as it is clinically very relevant. HVPG monitoring can be used to assess anti-viral therapy particularly in cirrhosis, ergonomically combined with transjugular biopsy. CONCLUSIONS: The prognostic and therapeutic value of HVPG is established beyond portal hypertensive bleeding for which there are some clinical surrogates. HVPG measurement should now be part of everyday clinical practice.

Long-term therapy with adefovir dipivoxil in hepatitis B e antigen-negative patients developing resistance to lamivudine.

BACKGROUND: The efficacy of long-term adefovir dipivoxil monotherapy or combination of adefovir and lamivudine in hepatitis B e antigen (HBe-Ag)-negative lamivudine-resistant chronic hepatitis B (CHB) patients is still under investigation. AIM: To assess the safety and efficacy of the long-term adefovir treatment alone or in combination with lamivudine in HBe-Ag-negative CHB patients who had developed breakthrough because of lamivudine-resistant mutants. METHODS: Fifty-nine patients received combination therapy, while 23 switched to adefovir alone after a 3-month course of combination therapy. RESULTS: The median follow-up after adefovir's onset was 31 (18-40) months. Baseline characteristics were similar between the two groups. At 12 and 24 months, 69% and 89% of patients receiving combination therapy and 73% and 82% of patients receiving adefovir monotherapy had serum HBV-DNA <10(4) copies/mL (P > 0.5). Normalization of alanine aminotransferase levels occurred in 81% and 79% of patients receiving combination vs. 61% and 53% receiving adefovir monotherapy at 12 and 24 months, respectively (P > 0.50). Virological breakthroughs because of adefovir-resistant mutants occurred in five patients under adefovir monotherapy and in none receiving combination therapy (P = 0.001). No one developed decompensated liver disease or hepatocellular carcinoma during follow-up. Re-introduction of lamivudine in adefovir-resistant patients achieved reduction in HBV-DNA and biochemical remission, but re-emergence of lamivudine mutants was observed in one patient after 7.5 months. CONCLUSION: In HBe-Ag-negative CHB patients with lamivudine resistance, adding adefovir to continuing lamivudine therapy maximizes anti-viral efficacy because of absence of viral resistance.

Clinical trial: The effect of somatostatin vs. octreotide in preventing post-endoscopic increase in hepatic venous pressure gradient in cirrhotics with bleeding varices.

BACKGROUND: Hepatic venous pressure gradient (HVPG) increases significantly after endoscopic therapy in patients with bleeding oesophageal varices, which may precipitate further haemorrhage. Whether vasoactive drugs can suppress these changes remains unknown. AIM: To investigate the efficacy of somatostatin when compared with octreotide in preventing the post-endoscopic increase in HVPG during acute bleeding and whether the changes affect outcome. METHODS: Thirty-three cirrhotics with bleeding varices were randomized to receive somatostatin (n = 17) or octreotide (n = 16) under double-blind conditions, soon after their admission. HVPG measurements were performed before and immediately after endoscopic treatment. RESULTS: In the somatostatin group, postendotherapy HVPG values did not change significantly when compared with pre-treatment values (18.9 vs. 17.2, P = 0.092). Conversely, in the octreotide group, HVPG increased significantly after endoscopy (18.2 vs. 20.8, P = 0.003). The probability of 6-week survival without treatment failure was significantly higher in the somatostatin group (P = 0.024). Post-endoscopic HVPG value was independently associated with 6-week failure. CONCLUSIONS: Somatostatin, but not octreotide, effectively prevents the post-endoscopic increase in HVPG, which may be associated with low probability of treatment failure.

The effects of glycosaminoglycans on coagulation: a thromboelastographic study.

Endogenous heparinoids impair coagulation, evidenced by thrombelastography in cirrhotic patients with bacterial infection, but it is not clear which glycosaminoglycans can be detected by native and heparinase-modified thrombelastography. To assess the effects of different glycosaminoglycans on thrombelastography parameters and the reversibility of these effects by heparinase-I-modified thrombelastography. Twenty volunteers were enrolled. Solutions of heparan sulphate, dermatan sulphate, and chondroitin-4-sulphate were prepared at 'equivalent' concentrations, based on the composition and anticoagulant activity of danaparoid. Serial dilutions of each glycosaminoglycan were prepared to achieve 1.0, 0.5, 0.1, and 0.05 U/ml. Native and heparinase-modified thrombelastography, anti-activated factor X activity and heparin cofactor II activity were evaluated at each concentration. A statistically significant heparin-like effect was seen with 1 and 0.5 U/ml heparan sulphate, and 1 and 0.5 U/ml dermatan sulphate, which was completely reversed by heparinase-modified thrombelastography. Anti-activated factor X activity was significantly increased in samples containing heparan and dermatan sulphates. The heparin cofactor II activity decreased with 1.0 and 0.5 U/ml dermatan sulphate and chondroitin-4-sulphate, but not with heparan sulphate. Heparan and dermatan sulphates affect haemostasis when added to whole blood in vitro, detectable by native thrombelastography and completely reversed by heparinase-I-modified thrombelastography. They may therefore be responsible for the heparin-like effect seen by thrombelastography in patients with cirrhosis and bacterial infection.

An evaluation of emergency sclerotherapy of varices in randomized trials: looking the needle in the eye.

BACKGROUND: The role of sclerotherapy for acute variceal bleeding is challenged by vasoactive drugs and by ligation. AIM: A meta-analysis was performed to evaluate whether sclerotherapy remains a gold standard in acute variceal bleeding. METHODS: Sclerotherapy was evaluated across four randomized trial groups: (a) combined with vasoconstrictors vs. vasoconstrictors alone (five trials, with 400 patients); (b) vs. vasoconstrictors alone (15 trials, with 1296 patients); (c) vs. combination of vasoconstrictors and sclerotherapy (eight trials, with 1026 patients); (d) vs. ligation (12 trials, with 1309 patients). We used the risk difference (absolute risk reduction) as our main effect measure. RESULTS: The efficacy of acute sclerotherapy was highest vs. ligation at 95 %, with a small advantage for ligation (an overtube was used in eight trials) of 2.5 % (95 % CI 0.4 % to 4.6 %) ( P = 0.018), but no survival difference. Efficacy of sclerotherapy combined with vasoconstrictors vs. vasoconstrictors alone was 86 %, whereas it was 83 % for sclerotherapy vs. vasoconstrictors alone. In both these groups sclerotherapy was superior for control of bleeding at, respectively, 16.3 % (95 % CI 8.7 % to 23.9 % ( P = 0.0001) and 5.9 % (95 % CI, 1.5 % to 10.3 %) ( P = 0.008), with increased survival in the latter. In the combination group of sclerotherapy with vasoconstrictors, the efficacy of sclerotherapy alone was 69 %, with the combination superior in controlling bleeding, at 13.2 % (95 % CI, 8.4 % to 18.1 %) ( P < 0.0001) but with no survival difference. CONCLUSION: This comparison of sclerotherapy across trials demonstrates a problem in defining its real efficacy. The conclusive evidence for substituting banding ligation or the combination of vasoconstrictors with sclerotherapy as better therapeutic approaches has not been provided in randomized trials. Sclerotherapy can remain a gold standard in variceal bleeding but there is scope for further studies of ligation and vasoactive drugs.

Rejection rates in a randomised trial of tacrolimus monotherapy versus triple therapy in liver transplant recipients with hepatitis C virus cirrhosis.

BACKGROUND: Reducing immunosuppression not only reduces complications but also may lessen recurrent hepatitis C virus (HCV) infection after liver transplantation. PATIENTS/METHODS: HCV-infected cirrhotic patients randomised to tacrolimus monotherapy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day, azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering over 3 months. RESULTS: Twenty-seven patients (MT) and 29 (TT)--median follow up 661 days (range, 1-1603). Rejection episodes (protocol/further biopsies) within first 3 months and use of empirical treatment were evaluated. New rejection was diagnosed if repeat biopsy (5-day interval) did not show improvement. Treated rejection episodes: 20 MT (15 biopsy-proven) vs. 24 TT (21 biopsy-proven), with 19 (MT) vs. 24 (TT) methylprednisolone boluses. Overall: 35 episodes (MT) and 46 (TT). Fewer MT patients had histological rejection (70%) than TT patients (86%), with fewer episodes of rejection (18.5% vs. 10%), and more moderate rejection (22% vs. 41%). The MT group had higher early tacrolimus levels. Rates of renal dysfunction, retransplantation, and death were not significantly different. CONCLUSION: Tacrolimus monotherapy is a viable immunosuppressive strategy in HCV-infected liver transplant recipients.

Transjugular liver biopsy: how good is it for accurate histological interpretation?

BACKGROUND: A transjugular liver biopsy (TJLB) specimen is often smaller or more fragmented than a percutaneous liver biopsy (PLB) specimen. Recently, for PLB, the minimum requirements to evaluate chronic hepatitis have been set at 20-25 mm length and > or =11 complete portal tracts. AIM: To evaluate and compare length of TJLB and PLB specimens, portal tract number, fragmentation and adequacy for histopathological diagnosis and staging. PATIENTS AND METHODS: 326 consecutive TJLB specimens in 274 patients (109 who had undergone a transplantation), always using three passes (19-G Tru-cut) and 40 consecutive PLB specimens (15-G Menghini). RESULTS: No technical failures occurred with the TJLB, and histological diagnosis was possible in 98.5%. The median (range) number of fragments was 5 (1-13) and the median total length was 22 (3-46) mm, with 65% of specimens > or =20 mm and 36% > or =25 mm; 60% of TJLB specimens were > or =28 mm long had > or =11 complete portal tracts. No difference in complete portal tract number or biopsy length was found between PLB and TJLB specimens. CONCLUSION: A TJLB specimen with three passes is adequate for histological diagnosis, with 89% of specimens being either > or =15 mm or having > or =6 complete portal tracts. Although adequate sampling remains a limitation for staging and grading of chronic hepatitis, TJLB is comparable to PLB in this respect.

Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with and without cavernous transformation.

BACKGROUND: Treatment options for patients with portal vein thrombosis are limited. AIM: To evaluate the feasibility and efficacy of transjugular intrahepatic portosystemic shunt for portal vein thrombosis with/without cavernomatous transformation. METHODS: A survey of such patients, referred for transjugular intrahepatic portosystemic shunt between 1994 and 2005, was performed. Success rates, complications, transjugular intrahepatic portosystemic shunt patency and clinical progression were examined. RESULTS: Transjugular intrahepatic portosystemic shunt was attempted in 28 patients (13 cirrhotics). Indications were: presurgery/transplantation (2), worsening of ascites (2), variceal bleeding (15 - 8 elective), refractory ascites (3), portal biliopathy (3) and portal vein thrombosis complicating Budd-Chiari syndrome (2). Transjugular intrahepatic portosystemic shunt was placed successfully in 19 of 28 (73%); 23 of 28 had complete portal vein thrombosis and 9 of 23 had cavernous transformation and transjugular intrahepatic portosystemic shunt was successfully placed in six of these. In the 19 patients with transjugular intrahepatic portosystemic shunt, the mean follow-up was 18.1 months (range 5-70): six patients had stent revisions; three had liver transplantation, one died of bleeding. Most cirrhotic patients had an improvement in the Child-Pugh score. In the failed transjugular intrahepatic portosystemic shunt group, two of nine died, and three had further bleeding. CONCLUSIONS: Transjugular intrahepatic portosystemic shunt should be considered for selected patients with symptomatic complete portal vein thrombosis with/without cavernous transformation, as clinical improvement and less rebleeding occur when transjugular intrahepatic portosystemic shunt placement is successful.

Lamivudine monotherapy in HBeAg-negative chronic hepatitis B: prediction of response-breakthrough and long-term clinical outcome.

BACKGROUND: Factors that predict response and breakthrough phenomenon to lamivudine monotherapy in patients with HBeAg-negative chronic hepatitis B have not been well defined. AIM: To determine pre-treatment and on treatment variables that predict initial response and breakthrough in patients with HBeAg-negative chronic hepatitis B receiving long-term lamivudine. METHODS: Seventy-nine patients, with chronic HBeAg-negative hepatitis B, who received lamivudine for a median of 31 months were included in the study. RESULTS: Initial virologic and biochemical response was observed in 73 (92%) and 70 (89%) patients, respectively, while 34 (47%) and 15 (21%) patients developed virological and biochemical breakthrough, respectively. High levels of necroinflammation in liver biopsy were associated with a higher probability of initial virological and biochemical response. Patients with pre-treatment serum hepatitis B virus DNA concentrations of more than 10(6) copies/mL were three times more likely to develop virologic breakthrough. Two patients died, one with baseline cirrhosis because of liver failure during biochemical breakthrough while the second death was liver and treatment unrelated. CONCLUSIONS: In HBeAg-negative chronic hepatitis B, initial response to lamivudine therapy is associated with necroinflammation, while baseline serum hepatitis B virus DNA exceeding 10(6) copies/mL is a strong predictor for breakthrough because of drug-resistant mutations. Severe complications are uncommon and are associated with biochemical breakthrough and pre-existing cirrhosis.

Obstructive jaundice secondary to neuroendocrine tumour in a patient with von Recklinghausen's disease.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, with variable clinical manifestations and unpredictable course, associated with an increased incidence of various tumours. Plexiform neurofibromas are hallmark lesions of NF1; they are slow-growing tumours, which account for substantial morbidity, including disfigurement and functional impairment, and may even be life-threatening. Neuroendocrine tumours (NETs), a rare diverse group of neoplasms, are occasionally associated with neurofibromatosis. Pancreatic NETs are tumours with an incidence of less than 1/100 000 population/year and complex patterns of behaviour, which often need complicated strategies for optimal management. We present the case of a young adult with NF1, having a unique concurrence of plexiform neurofibroma involving the liver with an ampullary NET, and we discuss step by step the management in a specialist centre.