CIRROSI E IPERTENSIONE PORTALE NELLA DONNA

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1 Cagliari, 16 settembre 2017 CIRROSI E IPERTENSIONE PORTALE NELLA DONNA Vincenza Calvaruso, MD, PhD Ricercatore di Gastroenterologia Gastroenterologia & Epatologia, Di.Bi.M.I.S. Università degli Studi di Palermo vincenza.calvaruso@unipa.it

2 The natural history of chronic liver disease Variceal hemorrhage Ascites Encephalopathy Jaundice Esophageal Varices < > 12 Hepatic Venous Pressure Gradient (HVPG) (mm Hg)

3 Precision Medicine What Is Precision Medicine? Treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. J. L. Jameson, D.L. Longo, NEJM, June 4, 2015

4 Gender differences in liver disease to..precision medicine Epidemiology Severity of disease/progression to cirrhosis Role of reproductive factors Outcome of cirrhosis and portal hypertension Management of portal hypertension Contraception and Pregnancy in liver cirrhosis

5 Male/ female ratio in patients with liver disease Cumulative HBV-negative Anti HCV+ HBsAg+ CAH 2.4/1 1.8/1 3.8/1 Cirrhosis 2.6/1 2.1/1 6.6/1 HCC 7.4/1 4.3/1 20.0/1 Villa et al., Cancer 1988 Primary biliary colangitis M/F ratio 1:10 Autoimmune hepatitis M/F ratio 1:3.6 Age at diagnosis higher in M than F (62 y vs 51 y) Durazzo M et al. WJG, 2014 Liver in gender medicine

6 Common causes of cirrhosis in women versus men Cirrhosis estimated by population-based study (UK) Women ALD Cryptogenic Autoimmune Viral hepatitis Men ALD Cryptogenic Viral hepatitis Autoimmune Cirrhosis estimated by those on waiting list for transplantation (US) Viral hepatitis Autoimmune NASH ALD Viral hepatitis ALD NASH Autoimmune Giard JM, Terrault NA. Women with Cirrhosis: Prevalence, Natural History, and Management. Gastroenterolog Clin N Am,2016

7 Fibrosis The natural history of chronic hepatitis C, from fibrosis to cirrhosis The natural history of chronic hepatitis C from Fibrosis to Cirrhosis Men HCV infected over 40 Women No alcohol HCV infected before 40 Yrs Acute Cirrhosis ESLD Poynard et al., Lancet 1997

8 Baseline Demographic, Laboratory, Metabolic and Histological Features of 1000 Patients with Chronic Hepatitis C According to Gender Variables Men (n=558) Women (n=442) Mean Age at enrolment - years 47.9± ±11.3 <.001 Mean Body Mass Index Kg/m ± ±3.8 <.001 Platelets count X 10 3 /mm ± ±66.5 <.001 Alanine Aminotransferase IU/L 98.6± ±67.4 <.001 GGT IU/L 57.1± ±37.3 <.001 Insulin µu/ml 6.1± ± HOMA-score 1.5± ± Length of HCV infection (years) 14,1 ±1.6 13,5 ± Histology at Biopsy Steatosis: <5% 5% to <20% 20% Grade of Inflammation (63.1) 150 (28.8) 42 (8.0) 391 (71.89) 128 (24.5) 4 (0.8) 261 (63.5) 116 (28.2) 34 (8.2) 332 (80.2) 74 (17.9) 8 (1.9) p Stage of Fibrosis (84.4) 82 (15.6) 372 (80.6) 43 (10.4).020 Cirrhosis 69 (12.3) 30 (6.7).003 Villa et al., Gastro 2011

9 Baseline Features of 670 Patients with Chronic Hepatitis C according to Gender Di Marco, Covolo, Calvaruso et al., JVH 2013

10 Risk factors for cirrhosis in ever-chronically infected women in anti-d cohort , Ireland Garvey P et al. J Hep 2017

11 Gender differences in chronic viral hepatitis Giard JM, Terrault NA. Women with Cirrhosis: Prevalence, Natural History, and Management. Gastroenterolog Clin N Am,2016

12 Gender differences in primary biliary colangitis and autoimmune hepatitis Primary biliary colangitis Autoimmune hepatitis Durazzo M et al. WJG, 2014 Liver in gender medicine

13 Gender differences in ASH and NASH Durazzo M et al. WJG,2014 Liver in gender medicine

14 Normal Testosterone and Estradiol levels throughout life (rough estimate) Testosterone in men Estradiol in women Age

15 Univariate and multivariate analysis for fibrosis in the women with chronic hepatitis C Villa et al, PlosOne 2012

16 Univariate and multivariate analysis for fibrosis in the whole cohort of patients with chronic hepatitis C. *Male as reference. HCV, hepatitis C virus; BMI, body mass index; ALT, alanine aminotransferase; GGT, c-glutamyl transpeptidase; OR, odds ratio; CI, confidence interval Villa et al, PlosOne 2012

17 Gender differences in liver disease to..precision medicine Epidemiology Severity of disease/progression to cirrhosis Role of reproductive factors Outcome of cirrhosis and portal hypertension Contraception and Pregnancy in liver cirrhosis

18 Baseline Characteristics of 444 patients with HCV cirrhosis according to the presence of EV Di Marco V, Calvaruso V. et al Gastroenterology 2017.

19 Baseline Characteristics of 1402 patients with HCV cirrhosis according to the presence of large EV Univariate logistic regression analysis OR 95%CI P value Multivariate logistic regression analysis OR 95%CI p value Age (Yrs) 0.99 ( ) ( ) 0.22 Male gender (%) 2.13 ( ) < ( ) BMI (Kg/m2) 1.03 ( ) Bilirubin 1.73 ( ) < Albumin 0.30 ( ) < INR 3.99 ( ) < Child Pugh score A B 4.03 ( ) < ( ) <0.001 AST 0.99 ( ) 0.35 Plt count (x 109) 1.00 ( ) < ( ) <0.001 PLT > (%) 0.17 ( ) < Portal vein (PV) mm* 1.24 ( ) < ( ) 0.87 PV < 12 mm* 0.39 ( ) < PV < 13 mm* 0.39 ( ) < Spleen diameter (SD) cm** 1.31 ( ) < ( ) LSM (mean, kpa) 1.03 ( ) < ( ) LSM < ( ) < Calvaruso V. Oral presentation AISF paper submitted

20 Predictors of HVPG reduction Riduzione HVPG 10 % 23 (76.7%) Assenza di Riduzione HVPG 10 % 7 (23.3%) p value Age (Yrs) Gender male female 14 (60.9) 9 (39.1) 2 (28.6) 5(71.4) AST ALT Bilirubina Albumina INR Plt count (x 109) MELD Portal vein (PV) mm* TE (kpa) Presenza of EV 19 (82.6) 6 (85.7) 0.97 Varici F2 1 (4.3) 2 (28.6) Calvaruso V. personal data

21 Clinical, biochemical and virological features of 444 patients with HCV related cirrhosis, according to liver decompensation (LD) occurrence 357 No LD 87 LD P value Adjusted O.R. (95% C.I.) p value (80.4%) (19.6%) Age 58.0 ± ± Sex (M) 218 (61.1%) 58 (66.7%) AST ± ± ALT ± ± GGT 82.6 ± ± PLT ± ± 35.0 < AP% 88.2 ± ± ( ) ( ) Bilirubin 1.0 ± ± ( ) Albumin 4.0 ± ± 0.5 < ( ) < SNP860 CC* 56 (29.6%) 11 (25.6%) TT/TC 133(70.4%) 32 (74.4%) Oesophageal varices 159 (44.5%) 69 (79.3%) < ( ) Diabetes 91(25.5%) 27(31.0%) SVR 103 (28.9%) 5 (5.7%) < ( ) Di Marco V, Calvaruso V. et al Gastroenterology 2017.

22 Clinical, biochemical and virological features of 444 patients with HCV related cirrhosis, according to HCC occurrence Adjusted O.R. (95% C.I.) p value 389 No HCC 55 HCC P value (87.6%) (12.4%) Age 57.7 ± ± Sex (M) 233 (59.9%) 43 (78.2%) ( ) ( ) AST ± ± ALT ± ± GGT 80.6 ± ± 67.6 < PLT ± ± AP% 87.9± ± ( ) ( ) ( ) Bilirubin 1.0 ± ± Albumin 4.0 ± ± SNP860 CC* 61 (30.3%) 6 (18.2%) TT/TC 140(69.7%) 25 (81.8%) Oesophageal varices 195 (50.1%) 33 (60.0%) Diabetes 106(27.2%) 12(21.8%) SVR 105 (27.0%) 3 (5.4%) < ( ) Di Marco V, Calvaruso V. et al Gastroenterology 2017.

23 Risk factors for HCC occurrence by Cox multivariate model Calvaruso V. et al Oral presentation EASL Paper submitted

24 Garvey P et al. J Hep 2017

25 Gender-dependent survival in HCC Overall survival of male and female patients with HCC Wen-Ming Cancer 1993 Survival after resection Tangkijvanich et al. WJG_2004 Ng Cancer 1995

26 Gender differences in liver disease to..precision medicine Epidemiology Severity of disease/progression to cirrhosis Role of reproductive factors Outcome of cirrhosis and portal hypertension Management of portal hypertension Contraception and Pregnancy in liver cirrhosis

27 Pre-primary, primary and secondary prophylaxis of variceal bleeding Baveno VI. Consensus Journal of Hepatology 2015 vol. 63 j

28 Gender effect on the NSBB treatment for portal hypertension. Burza MA.. Pharmacological Research2017

29 Gender differences in liver disease to..precision medicine Epidemiology Severity of disease/progression to cirrhosis Role of reproductive factors Outcome of cirrhosis and portal hypertension Management of portal hypertension Contraception and Pregnancy in liver cirrhosis

30 Contraception methods in women with cirrhosis:pros and cons Giard JM, Terrault NA. Women with Cirrhosis: Prevalence, Natural History, and Management. Gastroenterolog Clin N Am,2016

31 The outcomes of pregnancy in patients with cirrhosis Population-based study performed in Canada US Nationwide Inpatient Sample database Obstetric hospitalizations among patients with cirrhosis (n = 339) Obstetric hospitalizations among matched controls (n = 6625) Shaeen AAM et al. Liver International 2010 Feb;30(2):275-83

32 Model for end-stage liver disease score predicts outcome in cirrhotic patients during pregnancy No patient who had a MELD score 6 or a UKELD score 42 developed any significant hepatologic complications. Westbrook et al. Clin Gastroenterol Hepatol Aug;9(8):694-9.

33 Safety pharmacotherapy and procedured for portal hypertension during pregnancy

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35 Take home messages Cirrhosis is less frequent in women than in men, in a large part due to the lower prevalenceof HBV, HCV and alcohol abuse in women Fibrosis progression appears to be slower in premenopausal women than in men but with rates of progression equalizing in postmenopausal women. Women are at lower risk of HCC but rate of liver decompensation rate and response to beta blockers does not seems different in the two sex. Further studies are needed to assess if the etiological treatment of liver disease can influence the outcome of cirrhosis also according to gender.

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