CIRROSI E IPERTENSIONE PORTALE NELLA DONNA

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

The natural history of chronic liver disease Variceal hemorrhage Ascites Encephalopathy Jaundice Esophageal Varices < 5 5-10 12 > 12 Hepatic Venous Pressure Gradient (HVPG) (mm Hg)

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

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

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

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

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 0 5 10 13 15 20 25 30 35 40 Acute Cirrhosis ESLD Poynard et al., Lancet 1997

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±11.6 51.9±11.3 <.001 Mean Body Mass Index Kg/m 2 26.3±3.6 24.7±3.8 <.001 Platelets count X 10 3 /mm 3 179.0±56.5 203.4±66.5 <.001 Alanine Aminotransferase IU/L 98.6±87.4 73.4±67.4 <.001 GGT IU/L 57.1±52.4 37.1±37.3 <.001 Insulin µu/ml 6.1±3.5 10.0±6.4.093 HOMA-score 1.5±0.7 2.6±2.2.124 Length of HCV infection (years) 14,1 ±1.6 13,5 ±2.2.073 Histology at Biopsy Steatosis: <5% 5% to <20% 20% Grade of Inflammation 0-5 6-11 12-18 328 (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.95.99.99.018 Stage of Fibrosis 0-3 4-6 443 (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

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

Risk factors for cirrhosis in ever-chronically infected women in anti-d cohort 1977-1979, Ireland Garvey P et al. J Hep 2017

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

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

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

Normal Testosterone and Estradiol levels throughout life (rough estimate) 30 25 Testosterone in men Estradiol in women 20 15 10 5 0 25-34 35-44 45-54 55-64 65-74 75-84 Age

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

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

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

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 (0.98-1.00) 0.085 1.01 (0.99 1.03) 0.22 Male gender (%) 2.13 (1.42 3.19) <0.001 1.93 (1.19 3.14) 0.008 BMI (Kg/m2) 1.03 (0.98-1.07) 0.23 - Bilirubin 1.73 (1.40 2.12) < 0.001 - Albumin 0.30 (0.21 0.44) < 0.001 - INR 3.99 (2.19 7.28) < 0.001 - Child Pugh score A B 4.03 (2.67 6.08) < 0.001 2.58 (1.57 4.24) <0.001 AST 0.99 (0.99-1.00) 0.35 Plt count (x 109) 1.00 (1.00-1.00) < 0.001 1.00 (1.00 1.00) <0.001 PLT > 150000 (%) 0.17 (0.08 0.35) < 0.001 Portal vein (PV) mm* 1.24 (1.13-1.36) <0.001 0.99 (0.89-1.11) 0.87 PV < 12 mm* 0.39 (0.24-0.64) < 0.001 PV < 13 mm* 0.39 (0.26-0.58) < 0.001 Spleen diameter (SD) cm** 1.31 (1.22 1.40) < 0.001 1.15 (1.05 1.27) 0.004 LSM (mean, kpa) 1.03 (1.02-1.04) < 0.001 1.02 (1.01 1.03) 0.018 LSM < 20 0.42 (0.28 0.62) < 0.001 Calvaruso V. Oral presentation AISF 2017. paper submitted

Predictors of HVPG reduction Riduzione HVPG 10 % 23 (76.7%) Assenza di Riduzione HVPG 10 % 7 (23.3%) p value Age (Yrs) 63.8 60.1 0.47 Gender male female 14 (60.9) 9 (39.1) 2 (28.6) 5(71.4) AST 75.6 76.1 0.97 ALT 87.6 73.3 0.47 Bilirubina 1.0 1.4 0.09 Albumina 4.2 4.3 0.62 INR 1 1 0.59 Plt count (x 109) 111.1 79.3 0.036 MELD 7.3 8.6 0.11 Portal vein (PV) mm* 11.2 12.3 0.17 TE (kpa) 19.9 25.9 0.18 Presenza of EV 19 (82.6) 6 (85.7) 0.97 Varici F2 1 (4.3) 2 (28.6) 0.06 0.13 Calvaruso V. personal data

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 ± 8.7 57.8 ± 8.2 0.800 Sex (M) 218 (61.1%) 58 (66.7%) 0.334 AST 120.4 ± 66.2 125.1 ± 67.8 0.490 ALT 156.4 ± 84.6 145.4 ± 68.6 0.385 GGT 82.6 ± 41.2 81.8 ± 39.2 0.790 PLT 119.1 ± 45.1 87.4 ± 35.0 < 0.001 AP% 88.2 ± 14.2 84.1 ± 12.6 0.015 0.99 (0.98-0.99) 0.002 0.99 (0.98-1.01) 0.868 Bilirubin 1.0 ± 0.5 1.2 ± 0.5 0.001 1.44 (0.81-2.55) 0.211 Albumin 4.0 ± 0.4 3.7 ± 0.5 < 0.001 0.28 (0.14-0.54) < 0.001 SNP860 CC* 56 (29.6%) 11 (25.6%) 0.597 TT/TC 133(70.4%) 32 (74.4%) Oesophageal varices 159 (44.5%) 69 (79.3%) <0.001 2.54 (1.36 4.76) 0.004 Diabetes 91(25.5%) 27(31.0%) 0.383 SVR 103 (28.9%) 5 (5.7%) < 0.001 6.87 (2.29 20.55) 0.001 Di Marco V, Calvaruso V. et al Gastroenterology 2017.

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 ± 8.7 60.2 ± 7.3 0.044 Sex (M) 233 (59.9%) 43 (78.2%) 0.009 1.07 (1.03-1.13) 0.047 2.78 (1.32-5.83) 0.007 AST 112.4 ± 66.8 118.2 ± 64.8 0.940 ALT 144.4 ± 88.0 132.4 ± 68.6 0.480 GGT 80.6 ± 49.9 107.8 ± 67.6 < 0.001 PLT 115.1 ± 45.2 95.8 ± 39.7 0.002 AP% 87.9± 13.1 83.6 ± 18.2 0.040 1.39 (1.15-1.68) 0.001 0.99 (0.98-1.00) 0.05 0.98 (0.96-1.01) 0.145 Bilirubin 1.0 ± 0.5 1.1 ± 0.7 0.499 Albumin 4.0 ± 0.5 3.9 ± 0.4 0.106 SNP860 CC* 61 (30.3%) 6 (18.2%) 0.209 TT/TC 140(69.7%) 25 (81.8%) Oesophageal varices 195 (50.1%) 33 (60.0%) 0.201 Diabetes 106(27.2%) 12(21.8%) 0.385 SVR 105 (27.0%) 3 (5.4%) < 0.001 4.44 (1.30 15.11) 0.017 Di Marco V, Calvaruso V. et al Gastroenterology 2017.

Risk factors for HCC occurrence by Cox multivariate model Calvaruso V. et al Oral presentation EASL 2017. Paper submitted

Garvey P et al. J Hep 2017

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

Pre-primary, primary and secondary prophylaxis of variceal bleeding Baveno VI. Consensus Journal of Hepatology 2015 vol. 63 j 743 752

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

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

The outcomes of pregnancy in patients with cirrhosis Population-based study performed in Canada 1993 2005 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

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. 2011 Aug;9(8):694-9.

Safety pharmacotherapy and procedured for portal hypertension during pregnancy

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.