CIRROSI E IPERTENSIONE PORTALE NELLA DONNA

Vincenza Calvaruso, MD, PhDRicercatore di GastroenterologiaGastroenterologia & Epatologia, Di.Bi.M.I.S. Università degli Studi di Palermo vincenza.calvaruso@unipa.it

Cagliari, 16 settembre 2017

< 5 5-10 12 > 12

Hepatic Venous Pressure Gradient (HVPG) (mm Hg)

The natural history of chronic liver disease

•Variceal hemorrhage• Ascites• Encephalopathy• Jaundice

Esophageal Varices

Precision Medicine

What Is Precision Medicine?

Treatments targeted to the needs of individual patientson the basis of genetic, biomarker, phenotypic, or psychosocial characteristicsthat distinguish a givenpatient from other patientswith similar clinicalpresentations.

J. L. Jameson, D.L. Longo, NEJM, June 4, 2015

• 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

Gender differences in liver disease to…..precision medicine

Male/ female ratio in patients with liver disease

Cumulative HBV-negative 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

Anti HCV+

Primary biliary colangitis Autoimmune hepatitis

M/F ratio 1:10

Age at diagnosis higher in M than F(62 y vs 51 y)

M/F ratio 1:3.6

Durazzo M et al . WJG, 2014 Liver in gender medicine

Giard JM, Terrault NA . Women with Cirrhosis: Prevalence, Natural History, and Management.

Gastroenterolog Clin N Am,2016

Common causes of cirrhosis in women versus men

Women Men

Cirrhosis estimated by population-basedstudy (UK)

ALDCryptogenicAutoimmuneViral hepatitis

ALDCryptogenicViral hepatitisAutoimmune

Cirrhosis estimated by those on waiting list for transplantation(US)

Viral hepatitisAutoimmuneNASHALD

Viral hepatitisALDNASHAutoimmune

The natural history of chronic hepatitis C

from Fibrosis to Cirrhosis

Men

HCV infected

over 40

Acute Cirrhosis ESLD

Women

No alcohol

HCV infected

before 40

Fib

rosis

Yrs 0 5 10 13 15 20 25 30 35 40

Poynard et al., Lancet 1997

The natural history of chronic hepatitis C, from fibrosis to cirrhosis

Variables

Men

(n=558)

Women

(n=442) p

Mean Age at enrolment - years 47.9±11.6 51.9±11.3 <.001

Mean Body Mass Index – Kg/m2 26.3±3.6 24.7±3.8 <.001

Platelets count X 103/mm3 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

Stage of Fibrosis 0-3 4-6

Cirrhosis

328 (63.1)

150 (28.8) 42 (8.0)

391 (71.89)

128 (24.5)

4 (0.8)

443 (84.4) 82 (15.6)

69 (12.3)

261 (63.5)

116 (28.2) 34 (8.2)

332 (80.2)

74 (17.9)

8 (1.9)

372 (80.6) 43 (10.4)

30 (6.7)

.95

.99

.99

.018

.020

.003

Villa et al., Gastro 2011

Baseline Demographic, Laboratory, Metabolic and Histological Features of 1000 Patients with Chronic Hepatitis C According to Gender

Di Marco, Covolo, Calvaruso et al., JVH 2013

Baseline Features of 670 Patients with Chronic Hepatitis C according to Gender

Garvey P et al. J Hep 2017

Risk factors for cirrhosis in ever-chronically infected womenin anti-D cohort 1977-1979, Ireland

Giard JM, Terrault NA . Women with Cirrhosis: Prevalence, Natural History, and Management.

Gastroenterolog Clin N Am,2016

Gender differences in chronic viral hepatitis

Gender differences in primary biliary colangitis and

autoimmune hepatitis

Durazzo M et al . WJG, 2014 Liver in gender medicine

Primary biliary colangitis Autoimmune hepatitis

Gender differences in ASH and NASH

Durazzo M et al . WJG,2014 Liver in gender medicine

0

5

10

15

20

25

30

25-34 35-44 45-54 55-64 65-74 75-84

Testosterone in men

Estradiol in women

Normal Testosterone and Estradiol levels throughout life(rough estimate)

Age

Univariate and multivariate analysis for fibrosis in the womenwith chronic hepatitis C

Villa et al, PlosOne 2012

Univariate and multivariate analysis for fibrosis in the wholecohort of patients with chronic hepatitis C.

Villa et al, PlosOne 2012

*Male as reference. HCV, hepatitis C virus; BMI, body mass index; ALT, alanine aminotransferase; GGT, c-glutamyl transpeptidase; OR, odds ratio; CI,

confidence interval

• Epidemiology

• Severity of disease/progression to cirrhosis

• Role of reproductive factors

• Outcome of cirrhosis and portal hypertension

• Contraception and Pregnancy in liver cirrhosis

Gender differences in liver disease to…..precision medicine

Baseline Characteristics of 444 patients with HCV cirrhosis accordingto 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 malefemale

14 (60.9)9 (39.1)

2 (28.6)5(71.4)

0.13

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

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

(80.4%)

87 LD

(19.6%)

P valueAdjusted O.R. (95% C.I.) p value

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 < 0.0010.99 (0.98- 0.99) 0.002

AP% 88.2 ± 14.2 84.1 ± 12.6 0.0150.99 (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*

TT/TC

56 (29.6%)

133(70.4%)

11 (25.6%)

32 (74.4%)

0.597

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

389 No HCC

(87.6%)

55 HCC

(12.4%)

P valueAdjusted O.R. (95% C.I.) p value

Age 57.7 ± 8.7 60.2 ± 7.3 0.0441.07 (1.03-1.13) 0.047

Sex (M) 233 (59.9%) 43 (78.2%) 0.0092.78 (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 < 0.0011.39 (1.15 - 1.68) 0.001

PLT 115.1 ± 45.2 95.8 ± 39.7 0.0020.99 (0.98- 1.00) 0.05

AP% 87.9± 13.1 83.6 ± 18.2 0.0400.98 (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*

TT/TC

61 (30.3%)

140(69.7%)

6 (18.2%)

25 (81.8%)

0.209

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

Ng Cancer 1995

Survival after resection

Gender-dependent survival in HCC

Overall survival of male and

female patients with HCC

Tangkijvanich et al. WJG_2004

Wen-Ming Cancer 1993

• 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

Gender differences in liver disease to…..precision medicine

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

• 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

Gender differences in liver disease to…..precision medicine

Giard JM, Terrault NA . Women with Cirrhosis: Prevalence, Natural History, and Management.

Gastroenterolog Clin N Am,2016

Contraception methods in women with cirrhosis:pros and cons

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

Westbrook et al. Clin Gastroenterol Hepatol. 2011 Aug;9(8):694-9.

No patient who had a MELD score ≤ 6 or a UKELD score ≤ 42 developed

any significant hepatologic complications.

Safety pharmacotherapy and procedured for portal hypertensionduring 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 thanin men but with rates of progression equalizing in postmenopausalwomen.

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 liverdisease can influence the outcome of cirrhosis also according to gender.