«STEATOSI EPATICA ED EPATOPATIE METABOLICHE» Ester Vanni Division of Gastroenterology University of Turin

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1 «STEATOSI EPATICA ED EPATOPATIE METABOLICHE» Ester Vanni Division of Gastroenterology University of Turin

2 OUTLINE NAFLD overview NAFLD and menarche NAFLD and pregnancy NAFLD and menopause Other metabolic liver diseases Villasimius, spiaggia di Porto Giunco

3 NAFLD SPECTRUM Fatty Liver NASH Cirrhosis HCC Fat infiltration >5% with inflammation (lobular or portal) but without ballooning or with ballooning but without inflammation Steatosis + lobular inflammation + ballooning degeneration and/or fibrosis EASL-EASD-EASO Clinical Practice Guidelines, J Hepatol 2016

4 GLOBAL EPIDEMIOLOGY OF NAFLD: META- ANALYTIC ASSESSMENT OF PREVALENCE, INCIDENCE AND OUTCOMES The pooled overall NASH prevalence estimate among biopsied NAFLD patients was 59.10% (95% CI: ), with higher prevalence in Europe, Asia and North America. NASH prevalence estimates among NAFLD patients without an indication for biopsy were 6.67% (95% CI: ) for Asia and 29.85% (95% CI: ) for North America. Younossi et al, Hepatology 2016

5 STRONG ASSOCIATION WITH THE METABOLIC SYNDROME HDL-chol <40mg/dL in males, <50mg/dL in females Visceral obesity: 94 cm in males, 80 cm in females Elevated blood glucose: 100mg/dL or treated diabetes TG 150mg/dL or treated dyslipidemia Hypertension: 130/85mmHg or treated hypertension Angulo et al, Hepatology 1999 Dixon et al, Gastroenterology 2001 Argo et al, J Hepatol 2009 Neushwander-Tetri et al, Hepatology 2010

6 WORST PROGNOSIS: NASH AND ADVANCED FIBROSIS Pais (2013) and McPherson (2015) assessed the change in histological severity and evolving natural history of NAFLD using serial liver biopsies. NAFL may progress, with one quarter of patients developing bridging fibrosis over a relatively short time period. Pais et al, J Hepatol 2013 McPherson et al, J Hepatol 2015 Systematic review and meta-analysis of 11 paired-biopsy studies (411 patients). Annual fibrosis rates: 0.07 for NAFL, 0.14 for NASH 1 stage of progression over 14.3 years for NAFL, 7.1 years for NASH. Singh et al, Clin Gastroenterol Hepatol 2015 Longitudinal study: 229 biopsy-proven NAFLD patients, mean follow-up of 26.4 years (range 6-33). NAFLD patients had an increased mortality for cardiovascular disease HCC, infectious disease, and cirrhosis. Only patients with fibrosis stage 3-4, irrespective of NAS, had increased mortality (HR 3.3, P < 0.001). Ekstedt et al, Hepatology 2015 Retrospective analysis of 619 biopsy-proven NAFLD patients, median follow-up of 12.6 years (range ). 193 of the patients (33.2%) died or underwent liver transplantation, 26 patients (4.2%) developed liver-related events. Only fibrosis, regardless of steatohepatitis or NAS, was associated with worse outcomes, with a stepwise increased risk in higher stages (F3-F4). Angulo et al, Gastroenterology 2015

7 Following the introduction of centralized specialist teams to manage patients with cancer in England, the authors characterized the demographics of patients with HCC referred to the Newcastle-upon-Tyne Hospitals NHS Foundation Trust between 2000 and Regional HCC mortality data was from Public Health England. HCC related mortality in the region rose 1.8 fold in 10 years, from 2.0 to 3.7 per 100, cases were reviewed centrally, with 2 3 fold increases in referrals of patients with associated hepatitis C, alcoholic liver disease or no chronic liver disease and a >10 fold increase in HCC associated with non-alcoholic fatty liver disease (NAFLD). Dyson et al, J Hepatol 2014

8 ETIOLOGIES OF CHRONIC LIVER DISEASE ASSOCIATED WITH HCC Dyson et al, J Hepatol 2014

9 THE PREVALENCE OF METABOLIC RISK FACTORS IN PATIENTS WITH HCC IN NORTHERN ENGLAND MAJOR: OBESITY OR TYPE 2 DIABETES; MINOR: HYPERTENSION, ELEVATED TGS, REDUCED HDL CHOLESTEROL Dyson et al, J Hepatol 2014

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11 NAFLD AND MENARCHE

12 Ryu et al, J Hepatol 2015 AGE AT MENARCHE AND INCREASED RISK OF NAFLD Cross-sectional study: Korean women, aged 30 or older, from the Kangbuk Samsung Health Study Aim: examine the association between age at menarche and NAFLD, and to explore the role of adult adiposity or insulin resistance 9601 NAFLD subjects (assessed by US) Adjusting for adult BMI, percent fat mass and HOMA-IR, substantially reduced the identified associations, but they remained statistically significant

13 The association between age at menarche and NAFLD was modified by age: the adverse effect of early menarche on NAFLD was stronger in older women, while the protective effect of late menarche on NAFLD was observed only in younger women. Similar results were found exploring the association of age at menarche with the FLI, as a surrogate marker of NAFLD, and NAFLD fibrosis score (NFS), as non-invasive marker of liver fibrosis. Ryu et al, J Hepatol 2015

14 Prevalence of NAFLD (%) AGE AT MENARCHE AND INCREASED RISK OF NAFLD Cross-sectional study: 4128 postmenopausal Chinese women Aim: association between age at menarche and obesity, insulin resistance, and NAFLD after menopause. Ptrend=0.049 Ptrend= Ptrend= BMI < 25 (n=2102) 25>BMI<30 (n=1765) BMI >30 (n=151) An earlier age at menarche was associated with increased prevalence of NAFLD in later life, whereas a later age at menarche was associated with reduced prevalence of NAFLD. These associations were significantly attenuated after adjustment for current BMI or HOMA-IR Lu et al, J Diabetes 2016

15 CONCLUSIONS There is a significant association between earlier age at menarche and the prevalence of NAFLD The adverse effect of early menarche on NAFLD is partially mediated by adult adiposity and insulin resistance The biological mechanism linking earlier menarche with increased risk of NAFLD is poorly understood: an early maturation in women may reflect a longer duration of positive energy balance or a greater accumulation of body fat Obesity prevention strategies are needed in women with early menarche to reduce the risk of NAFLD

16 NAFLD AND PREGNANCY

17 ADVERSE OUTCOMES OF PREGNANCY IN WOMEN WITH NAFLD Study population Pregnancy outcomes Swedish Medical Birth Register (from 1973): data on 97 99% of all births in Sweden Focus on births in Sweden from 1992 to 2011 Three groups: NAFLD (n=110); higher prevalence of obesity and diabetes non-nafld/non-pcos (n= ) non-nafld/pcos (n=7909) Gestational diabetes Pre-eclampsia Gestational age (<37 weeks/ weeks) Cesarean section Apgar score Low birth weight (<2500 gr) Small for gestational age Congenital malformation Hagstrom et al, Liver International 2015

18 NAFLD VS NON-NAFLD/NON-PCOS Interaction between NAFLD and BMI with regard both pre-eclampsia and gestational diabetes Hagstrom et al, Liver International 2015

19 NAFLD PREDICTS DYSGLYCEMIA IN MID- PREGANCY Prospective cohort of 476 women enrolled in early pregnancy NAFLD assessed by US at weeks gestation Development of impaired fasting glucose, impaired glucose tolerance, or gestational diabetes at weeks gestation, determined by a fasting 75-g OGTT Adjusted for maternal age, ethnicity, family history of type 2 diabetes mellitus, body mass index at weeks gestation, and change in body mass index from to weeks gestation De Souza et al, AJG 2016

20 CONCLUSIONS NAFLD in pregnant women is associated with increased risks of pre-eclampsia and dysglycemia/gestational diabetes compared to the background population. Infants to women with NAFLD had an increased risk being born preterm and with low birth weight (<2500 g) Women with NAFLD should be monitored with extra care during pregnancy to avoid adverse outcomes.

21 GENDER DIFFERENCES BETWEEN PARENTAL PREGNANCY CHARACTERISTICS AND NAFLD IN ADOLESCENTS 1170 adolescent offspring aged 17-years participating in the Western Australian Pregnancy (Raine) Cohort Study Relationship between parental anthropomerty, pregnancyrelated and sociodemographic factors and future diagnosis of NAFLD in adolescent offsprings NAFLD diagnosed by US in 15.2% of the adolescents Adolescent females Adolescent males Pregnancy weight gain > 6kg by 18 weeks gestation Maternal pre-pregnancy obesity Maternal pre-pregnancy obesity Lower socio-economic status Adolescent central obesity Adolescent central obesity Ayonrinde et al, Hepatology in press

22 Maternal pre-pregnancy BMI and liver steatosis Paternal BMI and liver steatosis Ayonrinde et al, Hepatology in press

23 Maternal pre-pregnancy BMI and waist Maternal gestational weight gain by week 18 Ayonrinde et al, Hepatology in press

24 CONCLUSIONS Early life factors such as pre-pregnancy, maternal obesity and abnormal gestational weight gain have been associated with increased rates of obesity in the offspring Sexual dimorphism: after adjusting for adolescent obesity, maternal pre-pregnancy obesity and gestational weight gain >6 kg by week 18 independently predicted NAFLD in adolescent girls lower socioeconomic status at birth and to a lesser extent maternal pre-pregnancy obesity were independent predictors of NAFLD in adolescent boys Educating patients about the risk that parental obesity confers to their children should be incorporated into standard counseling. Strategies to protect against the risk of developing future NAFLD in offspring should ideally begin before pregnancy: normal parental BMI pre-pregnancy healthy maternal diet during pregnancy healthy first trimester weight gain IT S ALL ABOUT FAMILY! Ayonrinde et al, Hepatology in press

25 NAFLD AND MENOPAUSE

26 MENOPAUSE AND SEVERITY OF LIVER FIBROSIS 244 well-characterized females and age-matched males with biopsy-proven NAFLD Assess whether menopausal status is associated with the severity of liver fibrosis Lower levels of liver damage in menopausal NAFLD females that are undergoing HRT therapy compared with those that are not Turola et al, Disease Models & Mechanisms 2015

27 STEATOSIS MENOPAUSE AND SEVERITY OF LIVER FIBROSIS Experimental model Young and old male and female zebrafish overfed for 24 weeks Weekly BMI, histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis Protective role of estrogens and negative role of ovarian senescence in the development of hepatic fibrosis??? Turola et al, Disease Models & Mechanisms 2015

28 COLLAGEN PROPORTIONATE AREA % FIBROSIS Turola et al, Disease Models & Mechanisms 2015

29 CONCLUSIONS Menopause is associated with a significantly higher risk of relevant liver fibrosis ( F2) as opposed to childbearing women, even after adjustment for age, metabolic comorbidities, and histological features of NASH. The same negative effect of ovarian senescence and the protective effect of fertile age were also found in female zebrafish with experimental steatosis. A more intensive management should be planned for females with NAFLD in pre- and early menopause and the opportunity to use HRT to delay liver damage progression should be considered. Turola et al, Disease Models & Mechanisms 2015

30 OTHER METABOLIC LIVER DISEASES Porphyrias Glycogen storage diseases Inherited metabolic diseases, usually autosomal dominant, with low penetrance. Acute or chronic presentation. Acute porphyrias usually manifest after puberty, more frequently in women with a peak in the third decade. Very rare inherited recessive metabolic diseases caused by defects of enzymes involved in glycogen storage and disposal, involving the liver and the skeletal muscle. High prevalence of irregular menstrual cycles and polycystic ovaries Attacks occur particularly during periods of hormonal changes. Pregnancy is not contraindicated. Attacks are more frequent during early weeks of gestation, and in the immediate postpartum period. Significant excess risk of prenatal death, low birth weight and premature delivery has been observed. No fertility impairment in women with GSD type Ia/Ib, and IIIa/IIIb, the two more prevalent GSD. Good metabolic control prior to conception and maintained throughout gestation directly correlates with successful outcome in women with GSD AISF position paper on liver disease and pregnancy 2016

31 THANK YOU FOR YOUR ATTENTION

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33 OUTCOMES (STRATIFIED BY NAFLD AND NASH STATUS) Younossi et al, Hepatology 2016

34 NAFLD VS NON-NAFLD/PCOS Hagstrom et al, Liver International 2015