Presentación de PowerPointInfluencia del género en la fisiopatología, pronóstico y tratamiento de las
enfermedades hepáticas
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.
Clinical trials: study design & enrolment. Are females disadvantaged? (ILTS 2019, Toronto, Canada)
“….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
Summary of turning points in the regulation of women's participation in Clinical Trials
Chilet-Rosell E. Glob Health Action 2014, 7: 25484
*Include women in CTs *Results should be stratified by sex *Drug interactions with both endogenous and exogenous hormones should be studied
Bias in reporting sex and age in
biomedical research of
reports
Women are underrepresented
in CT (CVD)
Lancet 2019; 393eLife 2016;5e13615 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 seen more commonly in women; others in men
Some liver diseases only happen in pregnant
women
THE MOST CONCERNING IS ACCESS TO LT
Divergent impact of sex in advancement of liver injuries, diseases, and carcinogenesis
Frontiers In Bioscience, Scholar, 10, 65-100, 2018
Inhibitory effect of estrogen in fibrosis, cirrhosis and hepatocellular carcinoma
Liver disease in menopause
Brady CW. WJG 2015
Factores que influyen la progresión
Género femenino Factores genéticos (PNPLA3)
Cantidad y patrón de consumo de alcohol Infección VHC, VHB, VIH.
Obesidad Tabaco
(Adaptado con permiso. Mathurin P, Bataller R. J Hepatol 2015).
Steatosis
Steatohepatitis
Cirrhosis
- More advanced liver disease at time of diagnosis - More severe clinical course within a shorter time of alcohol abuse - 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: - 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 ?
Higher risk for ALD
Becker U; Hepatology 1996; Seitz HK, Nat Rev Dis Prim 2018; Osna NA, Alcohol Res 2017; Frezza M, NEJM 1990
Prediction of Risk of Liver Disease by Alcohol Intake, Sex, and Age: A Prospective Population Study
Becker U et al, Hepatology 1996; 23:1025-29
Prediction of risk of liver complications over 5 years in 4 profiles: normal liver, steatosis-F0-F2 or ASH-F0-F2 by noninvasive tests
All patients have been exposed to alcohol abuse for 15 years, have a BMI of 22 kg/m² and drink 150 g/d.
Prediction of risk of liver complications over 5 years in 4 profiles: steatosis-F3-F4 or ASH-F3-F4 by non-invasive tests
A Model to Identify Heavy Drinkers at High Risk for Liver Disease Progression
Delacôte C, Clin Gastroenterol Hepatol 2020
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):643-54
70% to 75% 25% to 30%
Steatosis with mild inflammation
Change in Fibrosis*[3,4]
*N = 108 pts with NAFL/NASH and median 6.6 yrs follow- up (data from serial biopsies).
Histological Subtypes[1,2]
Progression: 34-42%
Divergent 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, 2018
Steatosis
Steatohepatitis
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
lower prevalence of NAFLD and MS in postmenopausal women receiving hormonal therapy Clarck JM, Gastroenterology 2002
Hepatitis autoinmune
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; 63:644
CBP: estratificación de riesgo AI diseases
Diapositiva cedida amablemente por R. Andrade
Women are 20% less likely to undergo LT
Shorter Small body ≠ big liver
Less muscle mass Lower creatinine =
lower MELD
Gráfico1
Height
20
Unknown
40
To resize chart data range, drag lower right corner of range.
MELD Calculation
• Male, Age 55 (GFR 42 mL/min/1.73 m2 ) • MELD 28
• Bilirubin: 5.0 mg/dL • Creatinine: 1.77 mg/dL • INR: 2.0 • Sodium: 132 mEg/L
• Corrected MELD 28
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
Cholongitas et al. Am J Transplant 2007
Reduced access to LT in women: can be addressed by adding 1 MELD point Allen et al; Transplantation 2018
Gender differences in liver diseases
DILI 1:1.5
Better response to sorafenib Better survival in pre- menopause
*Isolated hepatic vein thrombosis *OCP-link risk *Higher rates acute presen
Higher prevalence of HNF1- alfa subtype
Older age at present & more severe disease
Buzzetti E; Pharmacological Research 2017; Serrano T & Berenguer M,
Earlier present & higher incidence liver injury
Worse outcome
Less severe
Summary
• The first step is acknowledging the problem – You have already done so by attending
the talk – Thank you for your attention!
Influencia del género en la fisiopatología, pronóstico y tratamiento de lasenfermedades hepáticas
Número de diapositiva 2
Número de diapositiva 3
Número de diapositiva 4
Número de diapositiva 5
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 
Proportion of deaths due to five causes of cirrhosis at global and regional levels by sex, 2017
Do Liver diseases affect women and men differently?
Divergent impact of sex in advancement of liver injuries, diseases, and carcinogenesis
Liver disease in menopause
Número de diapositiva 11
Número de diapositiva 12
Prediction of Risk of Liver Disease by Alcohol Intake, Sex,and Age: A Prospective Population Study
Número de diapositiva 14
Número de diapositiva 15
Número de diapositiva 16
Número de diapositiva 17
MELD Calculation
Summary