Influencia del género en la fisiopatología, pronóstico y tratamiento de las enfermedades hepáticas - AEEH
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Influencia del género en la fisiopatología,
pronóstico y tratamiento de las
enfermedades hepáticas
Clinical trials: study design & enrolment. Are females
disadvantaged? (ILTS 2019, Toronto, Canada)
What is normal?
“Over several centuries of medical and health
research, normal has, generally, been male”
The norm of the male body persists in much of medical education. A study of 31 anatomy textbooks used
between 1890 and 1989 found little difference in the proportions of anatomical drawings that were male
(about 70%) compared with female Another more recent survey of 15 general medical and surgical
textbooks found that 78% of depicted faces were male.
Summary of turning points in the regulation of
women's participation in Clinical Trials
*Include women in CTs
*Results should be stratified
by sex
*Drug interactions with both
endogenous and exogenous
hormones should be studied
“….women of childbearing age should not be included in the early phases
of CTs, until sufficient data on drug toxicity is obtained…”
In practice, this resulted in the exclusion of women from CTs
Chilet-Rosell E. Glob Health Action 2014, 7: 25484
Bias in reporting
Sex-related
sex and age in Gender bias in Women are
reporting in
biomedical clinical case underrepresented
medical research
research of reports in CT (CVD)
still inadequate
mouse models
eLife 2016;5e13615 Lancet 2019; 393 Plos One 2017;12(5) Eur Heart J. 2011 Jun;32(11)
J Am Coll Cardiol. 2008;19;52(8)
“…Importance of rigor and reproducibility in research, which includes blinding, randomization, replication, adequate sample size, and the importance of sex as a biological variable in experimental outcomes of preclinical, clinical, and population health studies”
The global, regional, and national burden of cirrhosis by cause in 195
countries and territories, 1990–2017: a systematic analysis for the
Global Burden of Disease Study 2017
www.thelancet.com/gastrohep
Proportion of deaths due to five causes of cirrhosis at global and
regional levels by sex, 2017
www.thelancet.com/gastrohep
Do Liver diseases affect women and men
differently?
Some liver diseases are Some liver diseases only
seen more commonly in happen in pregnant
women; others in men women
THE MOST CONCERNING
IS ACCESS TO LT
Some liver diseases are Does estrogen protect or
more severe in women harm the liver? Both!
Divergent impact of sex in advancement of liver
injuries, diseases, and carcinogenesis
Inhibitory effect of estrogen in fibrosis, cirrhosis and hepatocellular carcinoma
Frontiers In Bioscience, Scholar, 10, 65-100, 2018
Liver disease in menopause
Brady CW. WJG 2015Factores que influyen la progresión
Género femenino
Factores genéticos (PNPLA3)
Cantidad y patrón de consumo de alcohol
80-90% Infección VHC, VHB, VIH.
Obesidad
Hígado sano Tabaco
20-40%
Esteatosis
Fibrosis
8-20%
Cirrosis
20-40% 3-10%
Hepatitis Alcohólica
Figura 1 Descompensación HCC
(Adaptado con permiso. Mathurin P, Bataller R. J Hepatol 2015). (Infecciones)Higher risk for ALD
Steatosis
- More advanced liver disease at time of diagnosis
- More severe clinical course within a shorter time of alcohol abuse Steatohepatitis
- Greater risk of progression from hepatitis to cirrhosis after
abstaining from alcohol
- RR to develop alcoholic liver disease: 7.3 (vs 3.7)
- RR to develop cirrhosis: 17 (vs 7)
Greater susceptibility to alcohol-induced liver damage:
Cirrhosis
- Consume less alcohol
- Higher ethanol blood concentration
- Lower proportion of body water
- Lower ADH-dependent first pass metabolism in the gastric
mucosa
- Gender based differences in the sensitivity of hepatic KCs to
endotoxins generated in the gut ?
Becker U; Hepatology 1996; Seitz HK, Nat Rev Dis Prim 2018; Osna NA, Alcohol Res 2017; Frezza M, NEJM 1990Prediction of Risk of Liver Disease by Alcohol Intake, Sex,
and Age: A Prospective Population Study
Becker U et al, Hepatology 1996; 23:1025-29A Model to Identify Heavy Drinkers at High Risk for Liver Disease Progression Prediction of risk of liver complications over 5 years in 4 profiles: normal liver, Prediction of risk of liver complications over 5 years in 4 profiles: steatosis-F0-F2 or ASH-F0-F2 by noninvasive tests steatosis-F3-F4 or ASH-F3-F4 by non-invasive tests All patients have been exposed to alcohol abuse for 15 years, have a BMI of 22 kg/m² and drink 150 g/d. Delacôte C, Clin Gastroenterol Hepatol 2020
NAFLD
Histological Subtypes[1,2] Change in Fibrosis*[3,4]
NAFLD
70% to 75% 25% to 30% Regression:
18%-22%
Isolated
? Steatosis with ? NASH
steatosis mild inflammation Stable:
40%-43%
Cirrhosis ? Fibrosis
Progression:
34-42%
*N = 108 pts with NAFL/NASH and median 6.6 yrs follow-
up (data from serial biopsies).
1. Ludwig J, et al. Mayo Clin Proc. 1980;55(7):434-438.
2. Kleiner DE, et al. Hepatology. 2005;41(6):1313-1321.
3. McPherson S, et al. J Hepatol. 2015;62:1148-1155.
4. Singh S, et al. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54Divergent impact of gender in advancement of liver injuries,
diseases, and carcinogenesis: the example of NAFLD
Biswas S et al. Frontiers In Bioscience, Scholar, 10, 65-100, January 1, 2018Steatosis
Steatohepatitis
NAFLD more often affects men than women ….
Cirrhosis
yet among older ages, this difference is no longer
present
Men are at a higher risk of having more severe fibrosis compared to
women before menopause, while postmenopausal women have a similar
severity of liver fibrosis compared to men. These findings may be
explained by the protective effects of estrogen against fibrogenesis.
Yang JD, Hepatology 2014
Digestive and Liver Disease 47 (2015) 997–1006
Hepatology 2016
lower prevalence of NAFLD and MS in postmenopausal women receiving hormonal therapy
Clarck JM, Gastroenterology 2002AI diseases
Hepatitis autoinmune CBP: estratificación de riesgo
Epidemiología Afecta predominantemente a
mujeres
Adultos: 71-95% mujeres
Niños: 60-76% niñas
Embarazo:
Fármacos teratogénicos (MMF).
Riesgo de flare tras el parto
Mayor riesgo de osteoporosis en mujeres tras
menopausia (corticoides).
Mayor riesgo de otras enfermedades
autoinmunes concomitantes al diagnóstico en
mujeres que en hombres.
Evolución:
Hombres: menor edad al debut y mayor riesgo de
recaída (quizá en relación a mayor prevalencia de
HLA A1-B8-DR3)
Mujeres: peor supervivencia a largo plazo y mayor
necesidad de trasplante hepático
Durazzo et al. WJG 2014;20(9):2127-35
Al-Chalabi et al. J hepatol 2008;48(1):140-147
Trivedi PJ et al. Hepatology 2016; 63:644Diapositiva cedida amablemente por R. Andrade
Women are 20% less likely to undergo LT
Melk A….Berenguer M.; Transplantation 2019
WOMEN MEN
More hepatocellular
Shorter carcinoma =
Small body ≠ big liver Height MELD exception points
MELD
exceptions
Less muscle mass creatinine
Lower creatinine =
lower MELD• Male, Age 55 (GFR 42 mL/min/1.73 m2 )
• MELD 28
MELD Calculation • Bilirubin: 5.0 mg/dL
• Creatinine: 1.77 mg/dL
• INR: 2.0
• Sodium: 132 mEg/L
• Corrected MELD 28
Cholongitas et al. Am J Transplant 2007
Female, Age 55 (GFR 42 mL/min/1.73 m2)
• MELD 26
– Bilirubin: 5.0 mg/dL
– Creatinine: 1.40 mg/dL
– INR: 2.0
– Sodium: 132 mEg/L
• Corrected MELD 28
Reduced access to LT in women: can be addressed by adding 1 MELD point
Allen et al; Transplantation 2018Gender differences in liver diseases
DILI ALD AIH PBC PSC NAFLD HCC BSC Adenoma
HH
1:1.5 1.5-2:1 1:7-9 1:10 7:3 ??¿¿ 2-3:1 1.5:1 1:10
Better *Isolated
*Lower OH Increased hepatic vein
toxic incidence response to Higher
ALF Differential More sorafenib thrombosis prevalence
threshold after
response to symptoms Less severe menopause *OCP-link of HNF1-
Hepatitis- * Faster Better
therapy? (pruritus) survival in risk alfa
like fibrosis Higher incid
pre- *Higher rates subtype
progression diabetes/MS
menopause acute presen
Older age Earlier Combined Higher
Worse
at present Hepatic- prevalence
Better long outcome
present & higher inferior Of Beta
Chronic- term
injury like & more incidence cava veins catenin
outcome
severe liver thrombosis activation
disease injury
Buzzetti E; Pharmacological Research 2017; Serrano T & Berenguer M,Summary
• The first step is acknowledging the
problem
– You have already done so by attending
the talk
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