barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
32 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 33
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
NATURAL HISTORY OF ALD: ROLE OF ENVIRONMENTAL
AND GENETIC FACTORS
Felix Stickel
Bern, Switzerland
E-mail: Felix.stickel@ikp.unibe.ch
Studies in humans estimate that liver steatosis evolves in literally all excessive drinkers, complicated by
significant necroinflammation and fibrosis in only approximately one third, while 10% progress to cirrhosis
(1). Among the latter, 1-2% of patients per year develop hepatocellular carcinoma (HCC) as a severe
complication (2). This variable natural course is believed to derive from a complex interplay between
environmental and host risk factors (Figure 2).
Figure 2
KEY POINTS
• Alcoholic liver disease is a complex disease in which environmental and host factors modulate
evolution and progression of liver damage.
• Confirmed risk environmental factors for progressive ALD include quantities of alcohol, obesity,
and chronic coinfection with hepatitis viruses (B and C).
• Strong evidence supporting genetic background as an important modulator of susceptibility
for ALD.
• Lack of evidence for a role of HFE mutations in progression of ALD.
• Heterozygous and homozygous carriage of PNPLA3 rs738409 (G) allele is the first confirmed
genetic risk factor for ALD.
INTRODUCTION
Alcoholic liver disease (ALD) is a complex disease and accounts for the majority of chronic liver diseases in
Western countries. Development of ALD depends on long-term excessive drinking and other environmental,
individually acquired, and inherent modifying factors which interact over time to allow for or prevent ALD
development and progression (Figure 1). While many environmental factors are now well-characterized by
population-based and epidemiology studies, recent advances in our understanding of the role of genetic
variation in the phenotypic expression of diseases in man precipitated research activities for host genetic
factors that influence the course of many complex diseases, including ALD.
Figure 1
Non-genetic vs. genetic determinants of ALD progression
Risk factors for the development of progressive alcoholic fibrosis are commonly stratified into host (including
genetics) or environmental (non-genetic) modifiers. Crucial environmental factors that modulate the
development of ALD are the quantity of alcohol over time, the continuity of its abuse, and drinking patterns,
while gender, ethnic descent, co-existing metabolic syndrome or chronic viral hepatitis, and iron overload
are important host factors.
Obviously, the most crucial environmental factor is alcohol per se, displaying a clear dose-relationship
between the amount of alcohol and the likelihood of developing alcoholic cirrhosis (Figure 3). Crosssectional
studies have shown that alcoholic steatosis is encountered in approximately 60% of subjects who
drink >60g/day, and the risk of developing cirrhosis highest among those with a consumption of >120g/day
(1). In a meta-analysis, the risk of developing cirrhosis increased exponentially with a daily consumption
from 25g to 100g (3).
Figure 3
Unlike many other chronic liver diseases, ALD is a potentially avoidable disease since ALD does not develop
unless alcohol is consumed excessively. Thus, ALD only evolves if interventions against harmful drinking
do not take place, or fail. However, scientific and common cognition show that alcohol consumption per se
is not necessarily sufficient to elicit significant ALD since only a minority of heavy drinkers progresses to
severe ALD.