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