Milena Marietti

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.

Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease but the second cause of death among NAFLD patients are attributed to malignancies at both gastrointestinal (liver, colon, esophagus, stomach, and pancreas) and extra-intestinal sites (kidney in men, and breast in women). Obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers. NAFLD has an intertwined relationship with metabolic syndrome and significantly contributes to the risk of hepatocellular carcinoma (HCC), but recent evidence have fuelled concerns that NAFLD may be a new, and added, risk factor for extra-hepatic cancers, particularly in the gastrointestinal tract. In this review we critically appraise key studies on NAFLD-associated extra-hepatic cancers and speculate on how NAFLD may influence carcinogenesis at these sites.

Lactic acidosis during Entecavir treatment in decompensated hepatitis B virus-related cirrhosis

Lactic acidosis (LA) may be observed in cirrhotics hepatitis B irus (HBV) patients with impaired liver function during Entecavir ETV) treatment and Model for End stage Liver Disease (MELD) core has been suggested to directly correlate with LA development 1]. However some recent studies [2–4] reported a high efficacy and afety of ETV in decompensated cirrhosis. Thus the risk of LA with nucleos(t)ide analogues (NUCs) remains ontroversial and very few data are available about LA in HBV and on-HBV related cirrhosis with high MELD score and multi-organ ailure (MOF), expressed by Sequential Organ Failure Assessment SOFA) score. In our study we retrospectively evaluated the emergence of LA uring ETV in a small series of HBV decompensated cirrhotics with igh MELD score and MOF, comparing the results with a second roup of patients with non-HBV decompensated cirrhosis and simlar clinical features. Six naïve HBV decompensated patients were analysed (Group ). These 6 patients were matched with 6 non-HBV decompensated atients (Group B). LA was defined as hyperlactataemia (serum actate level > 2 mmol/L) with arterial pH < 7.30. The main clinical haracteristics of the patients are reported in Table 1.

Quantification of hepatitis B surface antigen with the novel DiaSorin LIAISON XL Murex HBsAg Quant: correlation with the ARCHITECT quantitative assays.

BACKGROUND Recent technologic innovations allow for quantitative assessment of hepatitis B surface antigen (HBsAg) levels in serum; this has been used to monitor the course of chronic HBV hepatitis (CHB) and predict treatment response. LIAISON-XL Murex HBsAg Quant assay (DiaSorin, Saluggia, I) is the newest immunoassay CE approved to quantify HBsAg. OBJECTIVES To compare LIAISON-XL performances with ARCHITECT-QT HBsAg (Abbott Diagnostics, IL, USA), as reference test. STUDY DESIGN Sequential serum samples (n=152) from 14 HBe-negative patients with CHB, the majority of them infected by HBV genotype D undergoing antiviral treatment, were retrospectively tested with both assays. The 2nd WHO Standard 00/588 for HBsAg was used as reference. RESULTS LIAISON-XL and ARCHITECT-QT correlated by r=0.95, p<0.0001; by Bland-Altman analysis agreement of mean difference was 0.21 ± 0.15 log 10 IU/mL, 95% CI: -0.07 to 0.5). Performance of LIAISON-XL against the 2nd WHO Standard was r=0.998, p<0.0001 (95% CI: 0.993-0.999) with results nearer to the expected WHO values compared to ARCHITECT-QT. Median baseline HBsAg level was similar with the two methods before antiviral treatment, throughout fluctuations of HBsAg level in treatment non-responders and during the decrease of HBsAg titer in treatment responders. Correlation between HBsAg levels and HBV DNA was statistically significant for both the two immunoassays (LIAISON-XL: r=0.4988, 95% CI: 0.3452-0.6264, p<0.0001; ARCHITECT-QT: r=0.480, 95% CI: 0.3233-0.6111, p<0.0001). CONCLUSIONS Correlation between HBsAg measurement with LIAISON-XL and ARCHITECT-QT was high. LIAISON-XL accurately quantified HBsAg in clinical samples at baseline or during antiviral therapy; it can be applied for HBsAg quantification in clinical practice and decision making in CHB.

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD‐NO) compared to those with obesity (NAFLD‐Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD‐NO and 15 NAFLD‐Ob) and 20 CTs without obesity, by gas chromatography–mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep‐IR; Hep‐IR = endogenous glucose production × insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD‐Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD‐NO subjects compared to CTs. Glutamate, tyrosine, and the GSG‐index were correlated with Hep‐IR. The GSG‐index correlated with liver enzymes, in particular, gamma‐glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG‐index, while only the new GSG‐index was able to discriminate fibrosis F3‐4 from F0‐2 in this cohort. Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG‐index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145‐158).

Usefulness of the index of NASH - ION for the diagnosis of steatohepatitis in patients with non-alcoholic fatty liver: An external validation study

The non‐invasive identification of steatohepatitis (NASH) in patients with Non‐Alcoholic Fatty Liver Disease is an unmet need in clinical practice. Index of NASH (ION) is a new tool for the prediction of NASH. We aimed to externally validate ION and to compare it with CK‐18. Since necroinflammation precedes fibrosis, we also tested ION in combination with non‐invasive tools for fibrosis.

Obesity: Childhood obesity: time bomb for future burden of chronic liver disease.

A recent study reports that being overweight in late adolescence is associated with an increased risk of liver-related morbidity and mortality later in life. These findings give further strength to the concerns for the deleterious effects of childhood obesity on liver health. Early prevention by screening and lifestyle modification should be advised by health policies.

Adipose tissue insulin resistance is associated with macrophage activation in non-diabetic patients with non-alcoholic fatty liver disease

M. Marietti 1, C. Rosso1, M. Gaggini2, C. Saponaro2, K. Kazankov3, E. Buzzigoli 2, H.J. Moller4, G.P. Caviglia1, M.L. Abate1, A. Smedile1, G.M. Saracco5,6, H. Vilstrup3, J. George5,6, H. Gronbaek3, A. Gastaldelli 3, E. Bugianesi1 1 Department of Medical Sciences, University of Torino, Torino, Italy 2 Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy 3 Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark 4 Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark 5 The Storr Liver Centre, University of Sydney and Westmead Hospital, Westmead, Australia 6 Department of Oncology, University of Turin, Turin, Italy

Endoscopic ultrasound in common bile duct dilatation with normal liver enzymes.

In recent years, the description of isolated bile duct dilatation has been increasingly observed in subjects with normal liver function tests and nonspecific abdominal symptoms, probably due to the widespread use of high-resolution imaging techniques. However, there is scant literature about the evolution of this condition and the impact of endoscopic ultrasound (EUS) in the diagnostic work up. When noninvasive imaging tests (transabdominal ultrasound, computed tomography or magnetic resonance cholangiopancreatography) fail to identify the cause of dilatation and clinical or biochemical alarm signs are absent, the probability of having biliary disease is considered low. In this setting, using EUS, the presence of pathologic findings (choledocholithiasis, strictures, chronic pancreatitis, ampullary or pancreatic tumors, cholangiocarcinoma), not always with a benign course, has been observed. The aim of this review has been to evaluate the prevalence of disease among non-jaundiced patients without signs of cytolysis and/or cholestasis and the assessment of EUS yield. Data point out to a promising role of EUS in the identification of a potential biliary pathology. EUS is a low invasive technique, with high accuracy, that could play a double cost-effective role: identifying pathologic conditions with dismal prognosis, in asymptomatic patients with negative prior imaging tests, and excluding pathologic conditions and further follow-up in healthy subjects.

Increased hepatic glucose production and insulin resistance in subjects with non-alcoholic fatty liver disease is associated to increased plasma concentrations of glucogenic amino acids

Increased hepatic glucose production and insulin resistance in subjects with non-alcoholic fatty liver disease is associated to increased plasma concentrations of glucogenic amino acids / Gaggini, M.; Carli, F.; Rosso, C.; Latta, V.D.; Ciociaro, D.; Marietti, M; Buzzigoli, E.; Abate, M.L.; Gambino, R.; Cassader, M.; Smedile, A.; Bugianesi, E.; Gastaldelli, A.. In: JOURNAL OF HEPATOLOGY. ISSN 0168-8278. 66(2017), pp. 163-163. ((Intervento presentato al convegno European Association for the Study of the Liver EASL 2017 tenutosi a Amsterdam nel 19-23 Aprile 2017. Original Citation: Increased hepatic glucose production and insulin resistance in subjects with non-alcoholic fatty liver disease is associated to increased plasma concentrations of glucogenic amino acids