epatopatie hbv e hcv correlate: effetto del genere sulla
TRANSCRIPT
Erica Villa
UC di Gastroenterologia, Azienda Ospedaliero-Universitaria di Modena
Padova, 11 Ottobre 2013
Epatopatie HBV e HCV correlate: effetto del
genere sulla storia naturale della malattia
Male/female ratio in patients with liver disease
Villa et al, Cancer 1988
Cumulative HCV HBV
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
Prevalence of hepatitis B surface antigen (HBsAg) positivity
worldwide
S. Shina and M.. Kumar; Hepatology Research 2010
350-400 million individuals worldwide are chronically infected with HBV: in regions of high
endemicity many of these are female of reproductive age who are source for perinatal
transmission
Distribution of Australia Antigen (HBsAg) by Gender
Marshall Islands, USTTPI
Male
Female
Total
Cebu, Philippines
Male
Female
Total
Manila, Philippines
Male
Female
Total
Cashinahua, Peru
Male
Female
Total
Total
Number
243
226
495
430
334
764
138
59
197
45
44
89
Number
Positive
19
14
33
27
10
37
6
3
9
10
6
16
Percent
Positive
7.8
6.2
6.7
6.3
3.0
4.8
4.3
5.1
4.6
22.2
13.6
18.0
Blumberg, et al, Amer. J. Human Genetics 18, 594, 1966
Parent’s response
To HBV
Either parent HBsAg + :
anti-HBs –
Both parents HBsAg - :
anti-HBs –
Both parents HBsAg - :
either parent anti-HBs +
Couples
(No.)
33
29
154
Live births
Male Females
60 (1.8 ± 0.2)
51 (1.8 ± 0.2)
24 (1.6 ± 0.1)
24 (0.7 ± 0.1)
35 (1.2 ± 0.2)
22 (1.4 ± 0.1)
Sex ratio
250 (161,429)*
146 (96,230)*
109 (91,131)*
PLATI, GREECE. NUMBER OF MALE AND FEMALE LIVE BIRTHS
ACCORDING TO THE RESPONSES TO HBV OF PARENTS
*In parentheses, the 5 percent confidence limits.
Blumberg, B.S. Sex differences in response to Hepatitis B Virus,
Arthritis and Rheumatism,22, 1261, 1979
Hepatitis B and Sex Ratio: Individual Level Estimates
Notes: This table shows sex ratios among the children of carrier and non-carrier parents in four regions. Data were collected by testing married women and, in all cases except for Greenland, their husbands for HBV. Detailed reproductive histories were also collected. The table represents all births to women in those samples, with generally more than one birth to each women. The last two studies (Greece 2 and France) were designed specifically to test the hypothesis that HBV affects offspring sex ratio, and were run after the original theory was expressed.
Location
Greenland
Greenland
Kar Kar Island
Kar Kar Island
Greece 1
Greece 1
Philippines
Philippines
Greece 2
Greece 2
France
France
HBV Status
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Sons
64
174
63
163
85
287
66
304
52
1006
20
149
60
194
54
206
46
255
41
301
30
955
12
122
Sex Ratio
1.07
0.90
1.17
0.79
1.85
1.13
1.61
1.01
1.73
1.05
1.66
1.22
Daughters
From Oster, E. 2004
EFFECTS OF VACCINATION PROGRAM
ALASKA
• High HBV prevalence among Alaskan Native
Americans; low among non-Native American
• Universal vaccination program (including catch-
up) instituted in early 1980s.
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
1996-20021991-19951986-19901980-1985
CHANGES IN SEX RATIO IN ALASKA BEFORE AND
DURING VACCINATION PROGRAM
1.16
1.14
1.12
1.1
1.08
1.06
1.04
1.02
1
Native American High HBV
Native American Low HBV
Non-Native American
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
Notes: Sex ratio is number of boys for each girl. Only countries with more than 15,000 people
used to caclulate HBV pravalence are included. Citations for each country are in Appendix B.
Se
x R
atio
at B
irth
SEX RATIO AND HEPATITIS, WORLD
Hepatitis Rate (%)
Brazil
Belarus
Bangladesh
Iran
Malaysia
Singapore
Israel
Pakistan
China
Mexico
Turkey
France
IrelandGreece
South Korea
Spain
Australia
Italy
PolandJapan
1.14
1.12
1.1
1.08
1.06
1.04
1.02
10 2 4 6 8 10 12 14 16
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
N. Amer &W. Europe
• HBV explains about 50% of the missing women overall:
over 90% in China, 11% in India
• Vaccination programs appear to decrease sex ratio
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
Gender and HBV infection
The long term serological course of asymptomatic HBV carriers and
development of HCC Alward WL, J Infect Dis 1985
In a cohort of 150 asymptomatic carriers during a mean f.u. 6.1 years,
both HBeAg/anti-HBe seroconversion and HBsAg clearance occurred
more frequently in females than males ( p <0.01 and 0.02 respectively)
Incidence and determinants of spontaneous seroclearance of HBeAg and
DNA in patients with CHB
Yang H-I, Clin Gastroent. and Hepatol 2012
In a cohort of 1289 HBV carriers, 439 of whom HBeAg positive, the factors
influencing HBeAg/anti-HBe seroconversion were female sex (p=0.002),
genotype B (p<0.001), pre-core 1896 (p=0.043), baseline ALT and HBV-
DNA. Female sex, on the contrary, did not influence the HBV-DNA
clearance
Presence/Absence of Chronic Hepatitis B by gender and age
0
10
20
30
40
50
60
23
45
6
7
8
N. o
f p
ati
en
ts
Age (by decades)
Brunetto MR, Roma 2012
Age
yearsPrevalence
VariationFemales Males
Prevalence
Variation
<30 0/8 0/26
31-40 1/31 (3.2%) 3/56 (5.4%)
41-50 3/43 (7.0%) 8/72 (11.1%)
51-60 3/38 (7.9%) 25/96 (26.0%)
61-70 10/27 (37%) 38/75 (50.7%)
71-80 8/16 (50%) 20/28 (71.4%)
≅ ≈ 2.5 x
≈ 2 x≈ 4.5 x
≈ 1.4 x≈ 1.3 x
Brunetto MR, Roma 2012
Prevalence of Cirrhosis by age
14
Risk Factors for HCC - Sex
Females
Males
Database ITA.LI.CA, 2008
Shimizu, 2007
Comparison of male-to-female ratio between two age groups of HBV-
related HCC patients without HCV infection.
< 50 yr
HCC incidence is 5 to 7-fold higher in males than females
Androgens
• Higher activities of androgen axis correlate with a higher risk of HCC
HBx protein enhances the transcriptional activity of the androgen
receptor in an androgen concentration dependent manner
Wu J-F et al, Gastroenterology 2010
• Androgen and its receptor enhance HBV replication in transgenic
mice Tian Y et al, J Virol 2012
Estrogens
• Estrogens can repress transcription of HBV genes by up-regulating
ER-α which interacts with and alters the binding of HNF-4 α to the
HBV enhancer 1
• This could account for lower viral load and reduced incidence of
HCC in women
Wang S-H et al, Gastroenterology 2012
HCV infection
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
rosi
s
Yrs 0 5 10 13 15 20 25 30 35 40
Poynard et al., Lancet 1997
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
Full reproductive (n. 123): i.e. women with regular menses and
<45 years of age)
Pre-menopausal (n. 38): women included in this group were
those who entered menopause 3 to 5 years after enrolment in
the study.
Early menopausal (n. 50): included in this group were women
menopausal from not more than 5 years from enrolment;
Late menopausal (n. 144): women that were menopausal since
at least 10 years.
Four groups of males, pair-matched by age in a 1:1 proportion,
were subsequently selected in order to have four perfectly
comparable pairs
Four groups of women selected according to timing of reproductive
phases
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.
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
Villa et al, PlosOne 2012
Comparison of the baseline independent predictive factors for fibrosis in the four
cohorts of patients with chronic hepatitis C.
TNF-alfa and IL-6 levels in fert ile and post-menopausal HCV+
women compared with males strat ified by age groups according to
females reproductive status.
Villa et al., Gastro 2011
Males Females Males Females
Late Post-Menopausal
Post-Menop.Nulliparous
Fertile Nulliparous
Early Post-Menopausal
Males <45 years
p<.001
p=.007 p=0.008
p<0.017
p<0.001 Controls
Fertile
Males 50-55 years
Males >60 years
Villa et al. Gastroenterology 2011
(A) Nulliparous women.
(B) Women with one or more past pregnancies.
(C) Women with one or more children.
(D) Women not taking oral contraceptives.
(E) Women with past or present use of oral
contraceptives.
(F) Nonmenopausal women.
(G) Menopausal women (total).
(H) Menopausal women receiving HRT.
(I) Menopausal women not receiving HRT.
Comparison of fibrosis progression rate (FPR) in HCV-infected
women according to past history of pregnancies, oral contraceptives,
menopause, and HRT.
*P .001; **P .02. NS, not significant.
Di Martino et al., 2004
TNF-α expression in the liver
Villa et al., Gastro 2011
p=<0.0001
p=0.02
p=0.023
(a) (b)
Negative/Weakly Positive
Moderate/Strongly Positive
Mean necro-inflammation and fibrosis scores in the 4 sub-groups of
female and age-matched male patients with
chronic hepatitis
Villa et al, PlosOne 2012
P<0.0001 P<0.0001 P<0.0001 NS
Estradiol Testosterone
E2/T Ratio
* P=0.013
* *
Estradiol and Testosterone serum levels and E2/T ratio in men and
women divided according to women’s reproductive
phases
Villa et al, PlosOne 2012
Gastroenterology, Modena
Nicola De Maria Barbara Lei Mariagrazia Del Buono
Filippo Schepis Anna Ferrari Stefano Gitto
Ranka Vukotic Veronica Bernabucci Ramona Zecchini
Aimilia Karampatou Elena Bertolini
Lab
Rosina Critelli Elena Turola Monica Luongo
Serena Marcorella Nazarena Raos Fabiola Milosa
Pathology, AOU, Modena
Luisa Losi, Livia Maccio
Clinical Pathology, NOCSAE, Modena
Tommaso Trenti Elisabetta Cariani
Simonetta Tagliavini Enrica Baraldi
Annamaria Cenci
Gastroenterology, Bari
Antonio Francavilla Alfredo Di Leo Maria Rendina
Castellana Grotte
Antonio Francavilla
WomenInHepatology
Courtesy of Anne Shreivogl
GENDER-C Project