Upload
doannhi
View
230
Download
0
Embed Size (px)
Citation preview
CIRROSI E IPERTENSIONE PORTALE NELLA DONNA
Vincenza Calvaruso, MD, PhDRicercatore di GastroenterologiaGastroenterologia & Epatologia, Di.Bi.M.I.S. Università degli Studi di Palermo [email protected]
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.