US researchers have suggested that liver diseases such as hepatitis and Alagille syndrome may be influenced by environmental factors, challenging the oft-made assumption that there is little to no link between liver disease and environmental components, according to a review published in Acta Pharmaceutica Sinica B. 

“Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology,” the authors of the study wrote. The current paradigm is that the risk of liver disease can be categorized broadly into 3 main categories: 

  • Risk modifiers: genetics, microbiome, health disparities, etc. 
  • Comorbidities: lifestyle, infection, drugs, etc. 
  • Primary cause(s): genetics, lifestyle, viral infection, drugs, etc. 

However, research is lacking on the effects of environmental exposure on disease penetrance and severity. Hence, the researchers of this study conducted a literature review to connect the dots between disparities in the phenotypes of liver diseases and potential influencing environmental factors. Their review described the possibility of environmental factors influencing a large number of liver diseases, including cholestatic liver disease, autoimmune hepatitis, drug-induced liver injury, fatty liver disease, and more.

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Let’s take a look at Alagille syndrome, for example. Alagille syndrome is an inherited disorder that results in bile duct paucity as well as cholestasis. Scientists have discovered that autosomal dominant variants in the Notch signaling pathway are responsible for the cholestatic aspect of this disease. However, despite the known genetic component of Alagille syndrome, its penetrance and severity have been observed to differ, even between family members. When this pattern is observed, it typically means that other factors (potentially environmental) are at play. 

Read more about Alagille syndrome prognosis

The researchers of this study proposed a few environmental factors that may be partly responsible for the disparities in liver disease severity. For example, the gut microbiome is known to play a key role in mediating health and disease. Given the close proximity of the liver to the gastrointestinal tract, it is not a stretch to suggest that it plays a role in liver disease etiology. Notably, an altered gut microbiome has been associated with every liver disease included in this review. In addition, studies have observed health disparities according to culture, socioeconomic status, and exposure to environmental hazards. 

The purpose of this review was not to draw a straight line between environmental factors and liver disease, but to invite questioning of long-held medical beliefs. As the authors of the study explain, “The purpose of this review is not to argue that all liver diseases have an environmental component, but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.” 


Beier JI, Arteel GE. Environmental exposure as a risk-modifying factor in liver diseases: knowns and unknowns. Acta Pharmaceutica Sinica B. Published online September 10, 2021. doi:10.1016/j.apsb.2021.09.005