E. Fatta

Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes

It is uncertain whether patients with nonalcoholic fatty liver disease (NAFLD) and normal alanine aminotransferase (ALT) have a milder disease and should undergo liver biopsy. We reviewed the histological data of 458 Italian patients with NAFLD in whom liver biopsy was indicated by altered liver enzymes (395 cases, 86%), or persistently elevated ferritin or long‐lasting severe steatosis (63 cases). Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis ≥ 2 were identified by multivariate analysis. Patients with normal ALT were significantly older, had lower body mass index, fasting triglycerides, insulin resistance according to homeostasis model assessment (HOMA‐IR), ALT, and gamma‐glutamyltransferase, but a higher prevalence of hypertension. NASH was diagnosed in 59% and 74% of the patients with normal and increased ALT, respectively (P = 0.01). In the overall series of patients, NASH was independently predicted by ALT (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.04–1.19 per 10‐IU/mL increase) and diabetes (OR, 1.5; 95% CI, 1.1–2.0). The same variables were selected in patients with increased ALT, whereas in those with normal ALT, HOMA‐IR and ALT were independent predictors. Severe fibrosis was independently predicted by serum ferritin (OR, 1.04; 95% CI, 1.001–1.08 per 50‐ng/mL increase), ALT (OR, 1.07; 95% CI, 1.02–1.14), and diabetes (OR, 1.8; 95% CI, 1.4–2.3) in the overall series, serum ferritin and diabetes in those with increased ALT, and only HOMA‐IR (OR, 1.97; 95% CI, 1.2–3.7) in patients with normal ALT. Conclusion: Normal ALT is not a valuable criterion to exclude patients from liver biopsy. Alterations in glucose metabolism and insulin resistance in subjects with normal ALT should also be considered in the selection of NAFLD cases for histological assessment of disease severity and progression. (HEPATOLOGY 2008.)

Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis.

BACKGROUND Insulin resistance is a key feature of nonalcoholic fatty liver disease. Patients with hereditary hemochromatosis, a disease characterized by progressive iron overload due, in most cases, to homozygosity for C282Y mutation in the HFE gene, have often decreased insulin sensitivity and release. AIMS To determine whether increased iron parameters/heterozygosity for the mutations of the HFE gene confer susceptibility to nonalcoholic fatty liver disease. PATIENTS One hundred and thirty-four consecutive Italian patients with clinical and ultrasonographic diagnosis of nonalcoholic fatty liver disease (82 with hyperferritinemia), half confirmed by liver biopsy. METHODS Insulin was determined by radioimmunoassay. HFE gene mutations were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS (1) Prevalence of C282Y HFE mutation was significantly higher in patients with nonalcoholic fatty liver disease compared to controls, the difference being more striking in patients with hyperferritinemia than in those without. (2) The presence of mild iron overload was associated with a lower insulin release. (3) Carriers of C282Y mutation developed nonalcoholic fatty liver disease despite lower body mass index and triglycerides. CONCLUSION The mild iron overload associated with heterozygosity for C282Y HFE mutation confers susceptibility to nonalcoholic fatty liver disease, causing relative insulin deficiency.

Serum ferritin levels are associated with vascular damage in patients with nonalcoholic fatty liver disease

BACKGROUND AND AIMS Increased ferritin and body iron stores are frequently observed in nonalcoholic fatty liver disease (NAFLD), associated with heightened susceptibility to vascular damage. Conflicting data have been reported on the role of iron in atherosclerosis, with recent data suggesting that excess iron induces vascular damage by increasing levels of the hormone hepcidin, which would determine iron trapping into macrophages, oxidative stress, and promotion of transformation into foam cells. Aim of this study was to investigate the relationship between iron status and cardiovascular damage in NAFLD. METHODS AND RESULTS Vascular damage was evaluated by common carotid arteries intima-media thickness (CC-IMT) measurement and plaque detection by ecocolor-doppler ultrasonography in 506 patients with clinical and ultrasonographic diagnosis of NAFLD, hemochromatosis gene (HFE) mutations by restriction analysis in 342 patients. Serum hepcidin-25 was measured by time-of-flight mass spectrometry in 143 patients. At multivariate analysis CC-IMT was associated with systolic blood pressure, glucose, LDL cholesterol, abdominal circumference, age, and ferritin (p=0.048). Carotid plaques were independently associated with age, ferritin, glucose, and hypertension. Ferritin reflected iron stores and metabolic syndrome components, but not inflammation or liver damage. Hyperferritinemia was associated with increased vascular damage only in patients with HFE genotypes associated with hepcidin upregulation by iron stores (p<0.0001), and serum hepcidin-25 was independently associated with carotid plaques (p=0.05). CONCLUSION Ferritin levels, reflecting iron stores, are independent predictors of vascular damage in NAFLD. The mechanism may involve upregulation of hepcidin by increased iron stores in patients not carrying HFE mutations, and iron compartmentalization into macrophages.

Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity

BACKGROUND & AIMS Increased visceral adiposity is considered the hallmark of the metabolic syndrome, whose hepatic manifestation is nonalcoholic fatty liver disease (NAFLD), although a subset of patients does not have visceral obesity. Our study aimed to compare metabolic alterations and liver damage in patients with NAFLD with and without visceral obesity. METHODS Four hundred and thirty one consecutive patients with liver biopsy-confirmed NAFLD were divided in three groups according to waist circumference, the simplest surrogate marker of visceral obesity. One hundred and thirty three patients (31%) had a waist circumference ≤94 (males) and ≤80 cm (females) (group A), 157 (36%) between 94 and 102, and 80 and 88 (B), and the remaining 141 (33%) had values higher than 102 and 88 cm (C). RESULTS Significant trends for older age, higher prevalence of female gender, lower HDL, higher triglycerides, altered glucose metabolism, hypertension, and metabolic syndrome were observed with increasing visceral adiposity. In contrast, non-alcoholic steatohepatitis (NASH) detected in 55% and 72% of patients with normal and increased waist circumference, respectively, and the presence of fibrosis ≥2 were not associated with visceral adiposity. Alanine aminotransferase (ALT), ferritin, HOMA-IR >4, and severe steatosis were independently associated with NASH, whereas ferritin and impaired glucose tolerance were associated with fibrosis ≥2. CONCLUSIONS Patients with normal waist circumference, despite milder metabolic alterations, may have NASH and are at risk of developing fibrosis, suggesting that once NAFLD is present, visceral obesity is not a major determinant of liver damage severity.

Liver cancer risk is increased in patients with porphyria cutanea tarda in comparison to matched control patients with chronic liver disease

BACKGROUND/AIMS Patients with porphyria and chronic liver disease could be at high risk of developing hepatocellular carcinoma. To define the incidence of primary liver cancer and identify variables associated with the risk of cancer in patients with porphyria cutanea tarda in comparison to control patients. METHODS Fifty-three patients with porphyria cutanea tarda were enrolled in a prospective study (median follow-up 72 +/- 54.1 months; range 12-216) and matched individually to a control case according to age (+/-5 years), sex, duration of follow up (+/- 5 years), severity of liver disease, and hepatitis C virus infection. RESULTS During follow-up hepatocellular carcinoma developed in 18 patients with porphyria and in four control patients. Incidence of primary liver cancer was 4.8 and 1.3 x 100 patients/year in the overall series of patients and of controls, respectively. The cumulative probability of being tumor free was significantly lower in porphyria cutanea tarda than in matched controls (75 vs 95%). Variables independently associated with the risk of liver cancer were the presence of porphyria and cirrhosis at enrollment (Odds ratios: 5.3, 95% CI 1.4-19.3 and 3.0, 95% CI 1.2-7.6, respectively). CONCLUSIONS Patients with porphyria are at higher risk of developing liver cancer than matched control patients.

A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia.

AIM To compare iron depletion to lifestyle changes alone in patients with severe nonalcoholic fatty liver disease (NAFLD) and hyperferritinemia, a frequent feature associated with more severe liver damage, despite at least 6 mo of lifestyle changes. METHODS Eligible subjects had to be 18-75 years old who underwent liver biopsy for ultrasonographically detected liver steatosis and hyperferritinemia, ferritin levels ≥ 250 ng/mL, and NAFLD activity score > 1. Iron depletion had to be achieved by removing 350 cc of blood every 10-15 d according to baseline hemoglobin values and venesection tolerance, until ferritin < 30 ng/mL and/or transferrin saturation (TS) < 25%. Thirty-eight patients were randomized 1:1 to phlebotomy (n = 21) or lifestyle changes alone (n = 17). The main outcome of the study was improvement in liver damage according to the NAFLD activity score at 2 years, secondary outcomes were improvements in liver enzymes [alanine aminotransferases (ALT), aspartate aminotransferase (AST), and gamma-glutamyl-transferases (GGT)]. RESULTS Phlebotomy was associated with normalization of iron parameters without adverse events. In the 21 patients compliant to the study protocol, the rate of histological improvement was higher in iron depleted vs control subjects (8/12, 67% vs 2/9, 22%, P = 0.039). There was a better improvement in steatosis grade in iron depleted vs control patients (P = 0.02). In patients followed-up at two years (n = 35), ALT, AST, and GGT levels were lower in iron-depleted than in control patients (P < 0.05). The prevalence of subjects with improvement in histological damage or, in the absence of liver biopsy, ALT decrease ≥ 20% (associated with histological improvement in biopsied patients) was higher in the phlebotomy than in the control arm (P = 0.022). The effect of iron depletion on liver damage improvement as assessed by histology or ALT decrease ≥ 20% was independent of baseline AST/ALT ratio and insulin resistance (P = 0.0001). CONCLUSION Iron depletion by phlebotomy is likely associated with a higher rate of improvement of histological liver damage than lifestyle changes alone in patients with NAFLD and hyperferritinemia, and with amelioration of liver enzymes.

Hepcidin resistance in dysmetabolic iron overload

Dysmetabolic iron overload syndrome (DIOS) is a frequent condition predisposing to metabolic, cardiovascular and hepatic damage, whose pathogenesis remains poorly defined. Aim of this study was to characterize iron metabolism in DIOS.

522 MAINTAINED VIRAL SUPPRESSION AND EXCELLENT SAFETY PROFILE OF ENTECAVIR MONOTHERAPY IN 418 NUC-NAÏVE PATIENTS WITH CHRONIC HEPATITIS B: A 4-YEAR FIELD PRACTICE, MULTICENTER STUDY

Angela Testa7, Pasquale Narciso7, Giorgio Antonucci7, Maria Vinci8, Giovambattista Pinzello8, Erika Fatta9, Silvia Fargion9, Paolo Del Poggio10, Barbara Coco11, Maurizia R. Brunetto11, Marco Andreoletti12, Agostino Colli12, Massimo Fasano14, Teresa Santantonio13, Guido Colloredo15, Luisa Pasulo16, Stefano Fagiuoli16, Alberto Eraldo Colombo17, Giorgio Bellati17, Francesco Fumagalli Maldini18, Maria Milanese18, Massimo Pozzi19, Natalia M. Terreni20, Giancarlo Spinzi20, Michela Quagliuolo21, Mauro Borzio21, Giovanna Lunghi22, Massimo Colombo1 Maintained viral suppression and excellent safety profile of entecavir monotherapy in 418 NUCnaive patients with chronic hepatitis B : a 4-year field practice, multicenter study

T-8 Entecavir monotherapy in 418 NUC-naive patients with chronic hepatitis B from field practice: high efficacy and favorable safety profile over 3 years of treatment

direct anti-hepatitis B agents; however, prevalence and clinical impact of this adverse event are poorly appreciated. Material and Methods: 124 patients (78% males, 58 yr, 60% cirrhosis, 14% with 2(OH)-vitamin D deficiency, 90% under tenofovir±lamivudine treatment for 15 months) underwent two dual energy X-ray absorptiometry (DXA) of the lumbar spine (LS) and femoral neck (FN) performed at least 12 months a part. A T score of less than -2.5 and a T score between -1 and -2.5 identified osteoporosis and osteopenia, respectively (WHO criteria). All patients lacked concomitant medication affecting bone metabolism or osteoporosi in the first DXA scan. Results: During a median interval of 15 months (12-50) between DXA scan, 13 (26%) of 50 (40%) patients with normal BMD at the first DXA scan progressed to osteopenia (3 at LS, 7 at FN and 3 at both LS and FN) but none to osteoporosis. Among the 74 (60%) patients with osteopenia at the first DXA scan, 5 (7%) progressed to osteoporosis (2 at LS, 2 at FN and 1 at both LS and FN). Overall, 77% of the patients had stable BMD, 8% improved and 15% worsened. Median LS and FN T scores remained stable between DXA scans (-0.70 vs -0.80; -1.10 vs -1.10, p=ns). Age, gender, BMI, cirrhosis, nucleotide treatment, duration of antiviral therapy, immunosuppression and vitamin D status were not associated with worsening of BMD. In conclusion, in patients with chronic hepatitis B under nucleos(t)ide therapy, BMD worsened in a minority of patients only.

OC.03.2 ENTECAVIR FOR NUC-NAÏVE CHRONIC HEPATITIS B PATIENTS IN CLINICAL PRACTICE: LONG-TERM EFFECTIVENESS FROM A LARGE MULTICENTER COHORT STUDY IN 376 PATIENTS

ENTECAVIR FOR NUC-NAIVE CHRONIC HEPATITIS B PATIENTS IN CLINICAL PRACTICE: LONG-TERM EFFECTIVENESS FROM A LARGE MULTICENTER COHORT STUDY IN 376 PATIENTS P. Lampertico ∗ ,1, M. Vigano1, F. Facchetti 1 , F. Suter 2, E. Minola2, O. Fracassetti 2 , G. Carosi 3, M. Puoti 3, G. Rizzardini 4 , G. Gubertini 4 , C. Magni4, G. Antonucci 5 , A. Testa5, P. Del Poggio6, S. Fargion7, E. Fatta7, M. Brunetto 8 , B. Coco8, A. Colli 9 , M. Andreoletti 9 , T. Santantonio10 , M. Fasano11, G. Colloredo12 , L. Pasulo13, M. Milanese14 , N. Terreni 15, M. Borzio16, R. Soffredini 1 , G. Lunghi17, M. Colombo1 11st Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, Policlinico, Mangiagalli, Regina Elena, University of Milan, Milan; 2Infectious Diseases, Ospedali Riuniti di Bergamo, Bergamo; 3Department of Infectious Diseases, University of Brescia, AO Spedali Civili, Brescia; 4I and II Division Infectious Diseases, Luigi Sacco Hospital, Milan; 5INMI, L. Spallanzani IRCCS, Rome; 6Ospedale di Treviglio, Treviglio; 7Internal Medicine 1b, Fondazione IRCCS Maggiore Hospital Policlinico, University of Milan, Milan; 8UO Epatologia, Azienda Ospedaliero-Universitaria Pisana, Pisa; 9S.C. Medicina Generale, Ospedale “A. Manzoni”, Lecco; 10Clinic of Infectious Diseases, University of Foggia, Foggia; 11Clinic of Infectious Diseases, University of Bari, Bari; 12Division of Medicine, Policlinico San Pietro, Bergamo; 13Gastroenterology Unit, Liver and Lung Transplantation Centre, Ospedali Riuniti di Bergamo, Bergamo; 14Liver Center, Clinica Medica, Azienda Ospedaliera S. Gerardo, Universita Milano Bicocca, Monza; 15UO Gastroenterologia, Ospedale Valduce, Como; 16UO Gastroenterologia, Azienda Ospedaliera di Melegnano, Melegnano; 17Institute of Preventive Medicine, Fondazione IRCCS Maggiore Hospital, University of Milan, Milan