Luisa Losi

Early Menopause Is Associated With Lack of Response to Antiviral Therapy in Women With Chronic Hepatitis C

BACKGROUND & AIMS Chronic hepatitis C (CHC) and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age. We investigated the associations among menopause, sustained virologic response (SVR), and liver damage in patients with CHC. METHODS We performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from CHC. Liver biopsy samples were analyzed (for fibrosis, inflammation, and steatosis) before patients received standard antiviral therapy. From women (n = 442), we collected data on the presence, type, and timing of menopause; associated hormone and metabolic features; serum levels of interleukin-6; and hepatic tumor necrosis factor (TNF)-α. RESULTS Postmenopausal women achieved SVRs less frequently than women of reproductive age (46.0% vs 67.5%; P < .0001) but as frequently as men (51.1%; P = .283). By multivariate regression analysis, independent significant predictors for women to not achieve an SVR were early menopause (odds ratio [OR], 8.055; 95% confidence interval [CI], 1.834-25.350), levels of γ-glutamyl transpeptidase (OR, 2.165; 95% CI, 1.364-3.436), infection with hepatitis C virus genotype 1 or 4 (OR, 3.861; 95% CI, 2.433-6.134), and cholesterol levels (OR, 0.985; 95% CI, 0.971-0.998). Early menopause was the only independent factor that predicted lack of an SVR among women with genotype 1 hepatitis C virus infection (OR, 3.933; 95% CI, 1.274-12.142). Baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6 (P = .04), and hepatic TNF-α (P = .007) were significantly higher among postmenopausal women than women of reproductive age. CONCLUSIONS Among women with CHC, early menopause was associated with a low likelihood of SVR, probably because of inflammatory factors that change at menopause.

Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD.

Differentiating steatosis from NASH is key in deciding treatment and follow‐up schedules. We hypothesized that sonographic grading of steatosis will correlate with metabolic and pathologic changes of NASH.

Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study

Objective The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC. Design Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model. Results Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54–82 days (n=20), 83–110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001). Conclusions The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC. Trial registration number ClinicalTrials.gov Identifier: NCT01657695.

Reproductive status is associated with the severity of fibrosis in women with hepatitis C.

Introduction Chronic hepatitis C is the main cause of death in patients with end-stage liver disease. Prognosis depends on the increase of fibrosis, whose progression is twice as rapid in men as in women. Aim of the study was to evaluate the effects of reproductive stage on fibrosis severity in women and to compare these findings with age-matched men. Materials and Methods A retrospective study of 710 consecutive patients with biopsy-proven chronic hepatitis C was conducted, using data from a clinical database of two tertiary Italian care centers. Four age-matched groups of men served as controls. Data about demographics, biochemistry, liver biopsy and ultrasonography were analyzed. Contributing factors were assessed by multivariate logistic regression analysis. Results Liver fibrosis was more advanced in the early menopausal than in the fully reproductive (P<0.0001) or premenopausal (P = 0.042) group. Late menopausal women had higher liver fibrosis compared with the other groups (fully reproductive, P<0.0001; premenopausal, P = <0.0001; early menopausal, P = 0.052). Multivariate analyses showed that male sex was independently associated with more severe fibrosis in the groups corresponding to premenopausal (P = 0.048) and early menopausal (P = 0.004) but not late menopausal pairs. In women, estradiol/testosterone ratio decreased markedly in early (vs. reproductive age: P = 0.002 and vs. premenopausal: P<0.0001) and late menopause (vs. reproductive age: P = 0.001; vs. premenopausal: P<0.0001). In men age-matched with menopausal women, estradiol/testosterone ratio instead increased (reproductive age group vs. early: P = 0.002 and vs. late M: P = 0.001). Conclusions The severity of fibrosis in women worsens in parallel with increasing estrogen deprivation and estradiol/testosterone ratio decrease. Our data provide evidence why fibrosis progression is discontinuous in women and more linear and severe in men, in whom aging-associated estradiol/testosterone ratio increase occurs too late to noticeably influence the inflammatory process leading to fibrosis.

Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels?

Hypothyroidism is associated with the risk of development of the metabolic syndrome (MS) and hypercholesterolemia. Direct evidence that hypothyroidism might be associated with advanced chronic liver disease via nonalcoholic steatohepatitis (NASH) is limited. We studied the relationship between thyroid hormones, thyroid stimulating hormone (TSH), cholesterol, and NASH. In consecutive euthyroid patients with biopsy-proven nonalcoholic fatty liver disease, TSH and thyroid hormone (FT3 and FT4) concentrations were compared in 25 patients with steatosis and 44 non-cirrhotic NASH patients featuring concurrent ballooning, lobular inflammation and steatosis. The MS was diagnosed according to ATP III criteria. A meta-analysis of previously published studies was performed to evaluate whether NASH, compared to simple steatosis, is associated with lower cholesterol levels. At univariate analysis, compared to those with steatosis, patients with NASH have a wider waist, elevated levels of BMI, ALT, AST, fasting insulin, HOMA-IR, ferritin, TSH and a lower serum cholesterol. At stepwise multivariable logistic regression analysis, the independent predictors of NASH are high HOMA and TSH and lower total cholesterol (Model 1); MS and high TSH (Model 2). At meta-analysis, serum total cholesterol levels are significantly lower in predominantly non-cirrhotic NASH than in simple steatosis. This study provides cross-sectional and meta-analytic evidence that, in euthyroid patients, high-though-normal TSH values are independently associated with NASH. Further work is needed to ascertain the role, if any, of lower cholesterol serum levels in assisting in the diagnosis of NASH.

Effects of bile duct ligation and cholic acid treatment on fatty liver in two rat models of non-alcoholic fatty liver disease

BACKGROUND Non-alcoholic fatty liver disease, one of the most prevalent liver disorders in Western countries, is characterized by hepatic accumulation of triglycerides. Bile acids have long been known to affect triglyceride homeostasis through a not completely understood mechanism. AIM To analyse the effects of two different manipulations of bile acid circulation on non-alcoholic fatty liver disease. METHODS Two animal models of non-alcoholic fatty liver disease were developed by either feeding rats with a choline deficient or with a high fat diet. After 4 weeks, rats were randomized to undergo either bile duct ligation, sham operation or cholic acid administration. RESULTS During cholestasis there was an increased CYP7A1 expression, the rate limiting enzyme in bile acid synthesis, and a reduction of hepatic concentration of oxysterols, ligands of the liver X receptors. Target genes of the liver X receptors, involved in fatty acid and triglyceride synthesis, were down-regulated in association with decreased hepatic triglyceride content and improvement of fatty liver. Administration of cholic acid, ligand of farnesoid X receptor, also had a beneficial effect on fatty liver in rats on choline deficient diet. CONCLUSION These results indicate that pharmacological approaches increasing the expression of CYP7A1 or stimulating farnesoid X receptor pathway could represent a promising treatment for non-alcoholic fatty liver disease.

Cystic Pancreatic Neuroendocrine Neoplasms with Uncertain Malignant Potential : Report of Two Cases

Neuroendocrine tumors of the pancreas (NETP) represent only 1%–2% of all pancreatic neoplasms. They can be classified as functioning or non-functioning, respectively, according to the presence or absence of paraneoplastic syndrome. Case 1 concerned a 70-year-old woman with a cystic lesion of the pancreatic head and body. All tumor markers were negative. The patient underwent a distal pancreatectomy. The histology revealed a well-differentiated endocrine tumor with uncertain malignant potential. Case 2 was a 61-year-old man with chronic polyserositis. The serum tumor markers were negative, while he was strongly positive for intracystic tumor markers carcinoembryonic antigen, carbohydrate antigen (CA) 19–9, and CA 125. The patient underwent a cephalo-pancreatic duodenectomy. The preoperative differential diagnosis of cystic NETP is still a challenge due to the high rate of the nonfunctional variant. Although cystic NETPs are well differentiated, they are still tumors with a malignant potential, and therefore an early diagnosis and radical surgical resection could be associated with a better long-term survival.

Hypervascular Retroperitoneal Mass in a Patient with Fever and Leucocytosis - Contrast-Enhanced Ultrasonographic Findings in a Case of Inflammatory Malignant Fibrous Histiocytoma

Einleitung ▼ Das entzündliche maligne fibröse Histiozytom (IMFH) ist der seltenste Subtyp der 5 histologischen Formen eines seltenen Weichteilsarkoms. IMFH sind zumeist retroperitoneal oder in den Bauchorganen bei älteren Patienten lokalisiert (Nascimento AF et al. J Surg Oncol 2008; 97: 330–339). Histologisch ist das IMFH durch ausgeprägte entzündliche Veränderungen, mit überwiegend neutrophiler und eosinophiler Infiltration charakterisiert, hinter denen sich große Zellen mit atypischen Merkmalen und nukleären Polymorphismen verbergen (Nascimento AF et al. J Surg Oncol 2008; 97: 330–339). Zum Diagnosezeitpunkt ist das IMFH in der Regel bereits eine voluminöse Raumforderung (Nascimento AF et al. J Surg Oncol 2008; 97: 330–339). Die Patienten stellen sich meist mit Fieber, unspezifischen Allgemeinsymptomen und entzündlicher Laborkonstellation vor. Erhöhte SerumC-reaktive Protein-(CRP) Werte und neutrophile Leukozytose sind sehr typisch (Melhem MF et al. Blood 1993; 82: 2038–2044). Eosinophile und leukämoide Reaktionen wurden seltener beschrieben. Die Krankheit verläuft typischerweise aggressiv. Weniger als 50 Fälle von IMFH sind bisher in der englischen Literatur beschrieben und es gibt kaum Daten zu charakteristischen Bildbefunden bei diesen Patienten. Der kontrastverstärkte Ultraschall (CEUS) ist nützlich zur Charakterisierung und Diagnose der häufigsten hepatischen Läsionen (Claudon M et al. Ultraschall in Med 2008; 29: 28–44), deutlich weniger ist über den US bei IMFH bekannt. Wir beschreiben zum ersten Mal frequenzbasierte Farbdoppler-Befunde, Spektraldoppler-Befunde und das CEUS-Muster eines retroperitoneal gelegenen IMFH.

Magnetic resonance for quantitative assessment of liver steatosis: a new potential tool to monitor antiretroviral-drug-related toxicities

BACKGROUND There is an increasing need for new diagnostic tools to monitor antiretroviral drug-related toxicities. Magnetic resonance (MR) imaging and MR spectroscopy are non-invasive diagnostic methods used in the detection and quantification of liver fat. The aim of this study was to compare sensitivity and specificity of different MR techniques in the quantitative assessment of liver steatosis, using liver biopsy as the reference standard, in patients with and without HIV infection. METHODS Sequentially evaluated patients with suspected steatosis who were referred for liver biopsy at our tertiary care site were eligible. MR liver fat content (LFC) was estimated by T2-weighted and fat-suppressed T2-weighted spin-echo, dual-phase T1-weighted gradient-echo, multiecho gradient-echo and (1)H spectroscopy. Association between LFC and histological steatosis percentage was calculated by using univariate linear regressions and Pearsons coefficient. Respective receiver operating characteristic (ROC) curves were used to compare specificity and sensitivity of MR methods in diagnosis (cutoff 5%) and in quantitative evaluation (cutoff 33%) of steatosis. RESULTS A total of 28 patients were identified: 12 refused or had contraindications for liver biopsy and 16 had biopsies plus MR. LFC and histological steatosis percentage were strongly associated (fat-suppressed r=0.86 [P<0.001], dual-phase r=0.88 [P<0.001], multiecho r=0.95 [P<0,001] and spectroscopy r=0.84 [P=0.01]). MR techniques had high sensitivity and specificity in diagnosis and quantitative assessment of steatosis (areas under ROC curves ranging from 0.88 to 0.98). CONCLUSIONS This pilot study confirms that MR may be a sensitive non-invasive alternative to biopsy for the quantitative assessment of liver fat and a potential end point to monitor antiretroviral-drug-related toxicities.

Peginterferon-Α_2B plus ribavirin is more effective than peginterferon-Α_2A plus ribavirin in menopausal women with chronic hepatitis C

Summary.  Under‐enrolment of women to randomized clinical trials, including chronic hepatitis C, has long been recognized. The aim of this study was to identify factors predictive of sustained virological response (SVR) to PEG IFN/Ribavirin antiviral therapy in relation to gender and reproductive status of female patients involved. Seven hundred and forty‐six treatment‐naïve patients (431 men, 315 women) treated with Peg‐IFNα‐2a (180 μg/week) or Peg‐IFNα‐2b (1.5 μg/kg/week) plus ribavirin (800–1400  mg/day) for 24 or 48 weeks were studied between 2006 and 2010. Differences in SVR rate, overall and by gender were assessed after adjustment and propensity score matching. SVR was obtained in 44.2% of Peg‐IFNα‐2a‐treated patients and in 51.2% of Peg‐IFNα‐2b‐treated patients (intention‐to‐treat; P = 0.139). Age, fibrosis stage and genotype 2 and 3 were independently associated with SVR by multivariate analysis. Analysing by gender, the difference in SVR between PEG‐IFNα types was not significant in men but highly significant in women (Peg‐IFNα‐2a:39.1%vs Peg‐IFNα‐2b:54.4%, P = 0.007). This was attributable to a higher SVR rate with Peg‐IFNα‐2b in the difficult postmenopausal population (26.9% Peg‐IFNα‐2a vs 46.0% Peg‐IFNα‐2b, P = 0.040). In women, absence of menopause, genotype 2 hepatitis C virus infection and use of Peg‐IFNα‐2b were independently associated with SVR. In conclusion, predictive factors for SVR are different in men and women. Factors differing between genders are menopause, severe steatosis and peg‐interferon used. The higher SVR rate with Peg‐IFNα‐2b in menopausal women is likely attributable to more favourable pharmacokinetics that allows Peg‐IFNα‐2b to reach visceral fat and oppose the increased cytokine production and enhanced inflammatory status in menopause.