Case Report: A Challenging Localization of a Pulmonary Ectopic ACTH-Secreting Tumor in a Patient With Severe Cushing's Syndrome.

Background: Ectopic adrenocorticotropic syndrome (EAS) is a rare cause of endogenous ACTH-dependent Cushing's syndrome, usually associated with severe hypercortisolism as well as comorbidities. Tumor detection is still a challenge and often requires several imaging procedures. In this report, we describe a case of an ectopic ACTH secretion with a misleading localization of the responsible tumor due to a concomitant rectal carcinoma. Case presentation: A 49-year-old man was referred to our Endocrinology Unit due to suspicion of Cushing's syndrome. His medical history included metastatic rectal adenocarcinoma, diagnosed 5 years ago and treated with adjuvant chemotherapy, radiotherapy and surgical resection. During follow-up, a thoracic computed tomography scan revealed two pulmonary nodules located in the superior and middle lobes of the right lung with a diameter of 5 and 10 mm, respectively. However, these nodules remained radiologically stable thereafter and were not considered relevant. All biochemical tests were suggestive of EAS (basal ACTH levels: 88.2 ng/L, nv 0-46; basal cortisol levels: 44.2 µg/dl, nv 4.8-19.5; negative response to CRH test and high dose dexamethasone suppression test) and radiological localization of the ectopic ACTH-secreting tumor was scheduled. The CT scan revealed a dimensional increase of the right superior lung nodule (from 5 to 12 mm). [68Ga]-DOTA-TOC PET/CT scan was negative, while [18F]-FDG-PET/CT showed a tracer accumulation in the superior nodule. After a multidisciplinary consultation, the patient underwent thoracic surgery that started with two atypical wedge resections of nodules. Frozen section analyses showed a neuroendocrine tumor on the right middle lobe nodule and a metastatic colorectal adenocarcinoma on the superior lesion. Then, a right superior nodulectomy and a right middle lobectomy with mediastinal lymphadenectomy were performed. The final histopathological examination confirmed a typical carcinoid tumor, strongly positive for ACTH. A post-surgical follow-up showed a persistent remission of Cushing's syndrome. Conclusions: The present report describes a case of severe hypercortisolism due to EAS not detected by functional imaging methods, in which the localization of ACTH ectopic origin was puzzled by a concomitant metastatic rectal carcinoma. The multidisciplinary approach was crucial for the management of this rare disease.

High rates of sustained virological response despite premature discontinuation of directly acting antivirals in HCV-infected patients treated in a real-life setting.

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1-4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.

Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis.

BACKGROUND & AIM: An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. PATIENTS AND METHODS: A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. RESULTS: During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47-6.57: p = 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23-7.51; p = 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05-3.44; p = 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08-4.09; p = 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35-6.09; p = 0.006) were associated with HCC recurrence. CONCLUSION: An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness. LAY SUMMARY: This prospective study focuses on the risk of developing de novo or recurrent hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment in patients with hepatitis C-related cirrhosis. We found that DAA treatment was associated with an early high HCC incidence in patients with undefined or non-malignant nodules, as well as in those with a history of complete response to HCC treatment. Whether this is related to the presence of clinically undetectable nests of cancer cells or to precancerous lesions that may progress to overt HCC upon DAA treatment remains unanswered. No evidence of increased clinical aggressiveness was reported in de novo or recurrent HCC.

Minimal increases of serum alpha-foetoprotein herald HCC detection in Caucasian HBV cirrhotic patients under long-term oral therapy.

BACKGROUND & AIMS: In Caucasian patients with compensated cirrhosis caused by hepatitis B virus (HBV), the risk of hepatocellular carcinoma (HCC) developing persist despite long-term nucleos(t)ide analogs (NUC) treatment. In the surveillance of this population with persistently normal transaminases because of NUCs, the added value of serum alpha-foetoprotein (AFP) monitoring is poorly defined. METHODS: Two hundred and fifty-eight Caucasian HCC-free patients with HBV-compensated cirrhosis who started tenofovir or entecavir while having normal serum AFP levels (≤7 ng/mL) at baseline or within the first year of treatment underwent HCC surveillance by semiannual ultrasound evaluation and serum AFP determination. RESULTS: During 96 (18-120) months of antiviral therapy, 3947 AFP values were collected, median AFP level was 2 ng/mL. Thirty-five patients developed an HCC at an overall 8-year crude cumulative incidence of 14% (annual incidence of 2%). HCC incidence increased in parallel with increasing AFP thresholds: 24%, 36%, 64% and 92% for AFP levels after exceeding 2, 4, 6 and 7 ng/mL for the first-time. Of the 12 patients who experienced an AFP rise > 7 ng/mL, 11 developed an HCC and one had liver metastases of lung cancer. Overall, an AFP > 7 ng/mL had 99.6% specificity, 31.4% sensitivity, 91.7% PPV, 90.2% NPV, LR+ 70.1 and LR- 0.69 for HCC; this excellent specificity was maintained up to 18 months before HCC detection. CONCLUSIONS: In Caucasian patients with HBV-compensated cirrhosis on long-term NUC, an increase in AFP over 7 ng/mL shows excellent specificity, heralding HCC development within 1 year.

Contrast imaging techniques to diagnose hepatocellular carcinoma in cirrhotics outside regular surveillance.

INTRODUCTION AND AIM: The American Association for the Study of the Liver (AASLD) recommends contrast computerized tomography (CT-scan) and magnetic resonance (MRI) to diagnose hepatocellular carcinoma (HCC) arising in cirrhotic patients under semiannual surveillance with abdominal ultrasound (US). A US guided fine needle biopsy (FNB) serves the same purpose in radiologically undiagnosed tumors and incidentally detected nodules in cirrhotics outside surveillance. In this population, we evaluated the performance of radiological diagnosis of HCC according to 2010 AASLD recommendations. MATERIALS AND METHODS: All cirrhotic patients with a liver nodule incidentally detected by US were prospectively investigated with a sequential application of CT-scan/MRI examination and a FNB. RESULTS: Between 2011 and 2015, 94 patients (mean age 67 years) had a liver nodule (total 120) detected by US in the context of histologically confirmed cirrhosis. Mean nodules diameter was 40 (10-160) mm, 87 (73%) <5cm. At histology, 84 (70%) nodules were HCC, 8 (7%) intrahepatic cholangiocarcinoma, 6 (5%) metastases, 2 (2%) neuroendocrine tumors and 20 (16%) benign lesions. Hyperenhancement in arterial phase followed by wash-out in venous phases on at least one radiological technique was demonstrated in 62 nodules (61 HCC, 1 high grade dysplastic nodule), with a specificity of 97% (IC95%: 85-100%), sensitivity 73% (IC95%: 62-81%) and diagnostic accuracy 80%, being 64% for ≥5cm HCC. Sensitivity of AFP >200ng/mL was 12% (IC95%: 6-23%). CONCLUSION: A single contrast imaging technique showing a typical contrast pattern confidently identifies HCC also in cirrhotic patients with an incidental liver nodule, thereby reducing the need for FNB examinations.

Evaluation of three "beyond Baveno VI" criteria to safely spare endoscopies in compensated advanced chronic liver disease.

BACKGROUND: Liver stiffness measurement (LSM) <20 kPa and platelet count >150,000/mm3 exclude varices needing treatment (VNT) in viral compensated advanced chronic liver disease (cACLD), saving-up to 20-25% endoscopies (Baveno VI criteria). Refinements of such criteria to further reduce endoscopies and an approach without LSM (Platelet 150/MELD 6) were later proposed. AIMS: To assess LSM 25/platelet 125, LSM 25/platelet 110 (Expanded-Baveno VI) and Platelet 150/MELD 6 accuracy versus Baveno VI criteria, and the impact of platelet count variability on criteria accuracy in all-etiologies cACLD. METHODS: cACLD patients undergoing screening endoscopy with laboratory data within 6 months and LSM within one year. RESULTS: Of 442 patients, 31% had varices (7% with VNT). Baveno VI criteria had 100% sensitivity (Se) and negative predictive value (NPV) and spared 19.5% endoscopies. "LSM 25/platelet 125" and "Expanded-Baveno VI" criteria maintained such accuracy, sparing 15% and 24% more endoscopies, respectively (p < 0.001). Platelet 150/MELD 6 was less accurate, misclassifying 10% VNT. Platelet count variability exceeded 8% and one VNT patient was misclassified with both "Expanded-Baveno VI" and "LSM 25/platelet 125" criteria considering the previous platelet count. CONCLUSIONS: Both "Expanded-Baveno VI" and "LSM 25/platelet 125" criteria are accurate in cACLD, but the former are more advantageous. Platelet 150/MELD 6 proved inadequate.

Lamivudine prophylaxis prevents hepatitis B virus reactivation in anti-HBc positive patients under rituximab for non-Hodgkin lymphoma.

BACKGOUND: A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation. AIMS: We wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication. METHODS: Eighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV. RESULTS: During 39 (2-108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression. CONCLUSION: LMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT.

Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir.

BACKGROUND AND AIMS: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. METHODS: A total of 103 TDF-treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD ) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter. RESULTS: During 46 (4-115) months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFRMDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P = 0.018). CONCLUSIONS: Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment.

Concomitant therapy with direct-acting antivirals and chemoimmunotherapy in HCV-associated diffuse large B-cell lymphoma.

INTRODUCTION: The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin's Lymphomas (NHL) is well established. Antiviral therapy (AVT) is the first-line treatment for HCV-related indolent NHL whereas diffuse large B-cell lymphoma (DLBCL) requires immediate start of chemoimmunotherapy (CIT), usually deferring AVT. However, an early HCV elimination may reduce the risk of CIT-induced liver toxicity and consequent CIT interruption or withdrawal. To date few data are available on safety and efficacy of concomitant administration of direct-acting antivirals (DAA) and CIT in HCV-associated DLBCL. METHODS: 7 consecutive patients (5 males, median age 65 years) with HCV infection (four genotype 2a/2c, two genotype 1b, one genotype 4; one patient with compensated cirrhosis) and DLBCL received different DAA regimens concurrently with CIT. RESULTS: All patients completed the scheduled AVT and CIT with neither interruption nor withdrawal of the latter. One case of neutropenia was observed during concomitant therapy, no liver toxicity occurred. All patients achieved sustained virological response and complete DLBCL response (median follow-up of 12 months). CONCLUSIONS: Concomitant administration of DAA and CIT for HCV-associated DLBCL is safe and may prevent CIT-induced liver toxicity. Large, prospective studies are needed to confirm these preliminary data and to assess prognostic implications.

Interleukin 28B genotype and insulin resistance in chronic hepatitis C patients.

BACKGROUND: In patients with chronic HCV infection, an association between IL28B genotype and insulin-resistance (IR), known predictors of sustained virological response (SVR) to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, has been reported. The aim of this study was to investigate the association of IR and IL28B genotype in two cohorts of well-characterized HCV patients. METHODS: A total of 480 non-diabetic HCV patients were analysed: 391 patients who received PEG-IFN/RBV in the MIST study and 89 previously reported patients followed at a metabolic liver diseases centre (Division of Internal Medicine, Fondazione IRCCS Ospedale Maggiore Policlinico, Milan, Italy). All were tested for IL28B rs12979860 single nucleotide polymorphism by real-time PCR and had IR measured by HOMA-IR. Staging of liver disease through liver biopsy was available for all patients. RESULTS: Overall, 164 patients (34%) were IL28B CC. Mean HOMA-IR values (±sd) did not differ according to IL28B genotype, being respectively 1.14 ±0.79 in CC versus 1.14 ±0.78 in CT/TT (P=1.0) in the first, and 2.4 ±1.0 versus 2.5 ±1.0 (P=0.7) in the second cohort. HOMA-IR>2 was not associated with IL28B genotype: 16/132 (12%) CC versus 31/259 (12%) CT/TT (P=1.0) in the first cohort and 16/32 (50%) versus 37/57 (65%; P=0.18) in the second. This held true also when using different HOMA cutoffs (>2.5, >3.0, >3.5 and >4.0). In the MIST cohort, HOMA-IR>2 did not influence treatment outcome, SVR rates being 28/47 (60%) in HOMA-IR>2 versus 214/344 (62%) in HOMA-IR≤2 (P=0.8). IL28B genotype was a strong predictor of SVR: 84% (111/132) in CC versus 51% (131/259) in CT/TT patients (P<0.0001). CONCLUSIONS: In two cohorts of non-diabetic HCV patients where IL28B genotype predicted treatment outcome, we found no association between IL28B genotype and HOMA-IR.

Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.

UNLABELLED: Steatosis has been reported to negatively influence the natural history of chronic hepatitis C (CHC), but controversy remains over its causal role due to the confounding effect of adiposity, insulin resistance, and diabetes. The rs738409 C>G patatin-like phospholipase domain-containing 3 (PNPLA3) single nucleotide polymorphism (SNP), encoding for the I148M protein variant, influences liver fat without affecting insulin resistance and body composition. The aim of this study was to evaluate the effect of the rs738409 CG genotype on liver fat and fibrosis in CHC patients. We also explored the possible effect of PNPLA3 genotype on other steatosis-related complications, namely, treatment failure and hepatocellular carcinoma (HCC) development. To this end we considered two independent series of 325 and 494 CHC patients with available DNA and liver biopsy followed at tertiary referral centers in northern Italy. The rs738409 genotype was determined by a Taqman assay. The rs738409 GG genotype, observed in 10% of patients, was associated with steatosis independently of age, sex, body mass index (BMI), diabetes, alcohol intake, and viral genotype (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.4-2.7; P < 0.001). The association with rs738409 genotype was confirmed for severe steatosis, was independent of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) values, and was observed in all viral genotypes but the 3. The rs738409 GG genotype was associated with fibrosis stage and cirrhosis (OR 1.47, 95% CI 1.2-1.9; P = 0.002), treatment response (n = 470; OR 0.63, 95% CI 0.4-0.8; P = 0.006), and HCC occurrence (n = 325; OR 2.16, 95% CI 1.3-3.6; P = 0.002), independently of confounders. CONCLUSION: The rs738409 PNPLA3 genotype influences steatosis development in CHC and is independently associated with cirrhosis and other steatosis-related clinical outcomes, such as lack of response to antiviral treatment and possibly HCC.

Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C.

BACKGROUND & AIMS: Transient elastography (TE) has gained popularity for the non-invasive assessment of severity of chronic viral hepatitis, but a comprehensive evaluation of the factors that might account for discrepancy in diagnostic accuracy between TE and the standard of care liver biopsy (LB) is still needed. METHODS: Patients with chronic hepatitis-B (HBV, n=104) or -C (HCV, n=453) underwent percutaneous LB concomitantly with TE (FibroScan®; Echosens, Paris, France). Liver cell necroinflammatory activity (A) and fibrosis (F) were assessed by METAVIR. Perisinusoidal fibrosis was rated with a 0-3 score. Determinants of TE results were investigated by a linear regression model whereas discordance between TE and LB results was assessed by logistic regression. RESULTS: Fibrosis (p<0.0001) and liver cell necroinflammatory activity (p<0.0001) were independently associated with TE results in both HBV and HCV patients, whereas steatosis (p<0.0001) was independently associated with TE in HCV only. Fibrosis overestimation was predicted by severe/moderate necroinflammatory activity in HBV and by older age (41-60 or>60years vs.<40), >2 UNL AST and>2 UNL GGT, as well as severe/moderate necroinflammatory activity and severe/moderate steatosis in HCV. In the latter patients, however, moderate/severe necroinflammatory activity and steatosis were the only independent predictors of fibrosis overestimation. CONCLUSIONS: Fibrosis and necroinflammatory activity are the main determinants of TE in chronic viral hepatitis. Since TE staging of fibrosis is influenced by necroinflammatory activity and steatosis, a diagnostic LB is deemed necessary for a reliable intra-patient TE monitoring of the course of viral hepatitis.

A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma.

BACKGROUND & AIMS: Chronic infection with hepatitis Delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC); predictors of disease outcome are, however, poorly defined. We tracked the course of HDV infection in 299 patients over a mean period of 233 months. METHODS: We analyzed data from patients who had been HDV positive for at least 6 months (230 males; mean age, 30 years) admitted from 1978 to 2006 to Maggiore Hospital, Milan. HDV infection was defined by the presence of HDV antigen in liver tissue or serum HDV RNA in anti-HDV/hepatitis B surface antigen seropositive patients. At enrollment, 7 patients had acute hepatitis, 101 had mild-moderate chronic hepatitis, 76 had severe chronic hepatitis, and 104 had histologic or clinical cirrhosis. Ninety patients were treated with interferon, 62 with corticosteroids, and 12 with nucleoside analogues; 135 received no therapy. RESULTS: Over a mean period of 233 months, 82 patients developed cirrhosis. Among the 186 total patients with cirrhosis, 46 developed HCC, 43 ascites, 44 jaundice, and 1 encephalopathy. Female sex, alcohol abuse, and HDV replication were associated with liver decompensation; HBV replication and interferon were associated with HCC development. By the end of the study, 186 patients were still alive, 63 had died, and 29 had received liver transplants. The main cause of death was liver failure (n = 37, 59%); HDV replication was the only independent predictor of mortality. CONCLUSIONS: Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality.

Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C.

Conflicting data exist regarding the relationship between hepatitis C virus genotype 1 and hepatic steatosis as well as the latter's role in the progression of fibrosis and treatment response. We assessed factors associated with hepatic steatosis in genotype 1 chronic hepatitis C and the impact of hepatic fat on fibrosis development and interferon responsiveness. Two hundred ninety-one non-diabetic patients with genotype 1 chronic hepatitis C were examined for the presence of steatosis and its correlation with clinical, virological, and biochemical data, including insulin resistance (IR), evaluated by the homeostasis model assessment (HOMA) score. Steatosis was graded as mild (1%-20% of hepatocytes involved), moderate (21%-40% of hepatocytes involved), and severe (>40% of hepatocytes involved). Steatosis was mild in 110 of 291 (37.8%) and moderate/severe in 55 of 291 (18.9%) subjects. By logistic regression, moderate/severe steatosis was independently associated with the female sex (odds ratio [OR] 2.74; 95% CI 1.40-5.35), high gamma-glutamyltransferase levels (OR 1.52; 95% CI 1.22-1.91), and HOMA-score (OR 1.076; 95% CI 1.001-1.26). By logistic regression, moderate/severe steatosis (OR 2.78; 95% CI 1.21-6.4), and platelet counts (OR 0.97; 95% CI 0.96-0.98) were independent predictors of advanced fibrosis. Patients with moderate/severe steatosis had an OR of 0.52 (95% CI 0.30-0.90) for sustained virological response compared with patients with mild/absent steatosis. In conclusion, in nondiabetic European patients with genotype 1 hepatitis C at low risk for the metabolic syndrome, the prevalence of steatosis was nearly 60%. IR is a risk factor for moderate/severe steatosis, especially in men. Moderate/severe steatosis has clinical relevance, being associated with advanced fibrosis and hyporesponsiveness to antiviral therapy.

Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: a randomized controlled trial.

BACKGROUND/AIMS: We assessed the effectiveness and safety of an induction dose of peginterferon alfa-2b (PEG-IFN) plus ribavirin for initial treatment of patients with genotype 1 chronic HCV infection in a randomized, controlled, multicenter trial. METHODS: Three hundred and eleven naïve patients infected with genotype 1 and chronic hepatitis were randomly assigned to 48-week treatment with PEG-IFN once weekly (80-100 micrograms depending on body weight for 8 weeks, followed by 50 micrograms for the next 40 weeks), or standard interferon alfa-2b (IFN) 6 million units on alternate days, both in combination with ribavirin (1000-1200 mg/day). RESULTS: PEG-IFN plus ribavirin significantly increased sustained virological response (SVR) compared with IFN plus ribavirin (41.1 vs. 29.3% respectively, P=0.030). Less patients discontinued PEG-IFN than IFN (19 vs. 31%, P=0.010). By logistic regression, SVR in the PEG-IFN group was independently associated with age <50 years, and mild fibrosis at liver biopsy. CONCLUSIONS: Combination therapy with an induction dose of PEG-IFN was a more effective and better tolerated treatment for naïve patients with genotype 1 than combination therapy with high dose standard IFN. In patients aged less than 50 years with mild fibrosis this schedule achieves a very high rate of SVR.