A study reveals sex differences in experimental liver cirrhosis

Researchers at Germans Trias i Pujol Research Institute (IGTP) have led a study that evaluates, for the first time, the difference between sexes in advanced liver disease in a rat model. The study has been published in the journal Laboratory Animals and has been conducted at the facilities of the Centre for Comparative Medicine and Bioimage of Catalonia (CMCiB), which is part of the European network of 3R centres and supports researchers in achieving refinement in animal models, following the values of responsible research to improve people's health.

When an organ is injured, our body initiates a healing process. If the injury is repeated or chronic, it can lead to an excessive accumulation of fibrous tissue and cause alterations in the structure and function of the affected organ. This phenomenon is known as fibrosis.

Fibrosis can affect organs such as the kidneys, lungs, heart and liver. For the latter, advanced fibrosis can progress to liver cirrhosis, the later and irreversible stage of liver disease, where secondary complications such as ascites, an accumulation of fluid in the abdomen, occur.

Scientific evidence shows that there are differences in the development and progression of liver disease between men and women. Oestrogens seem to play a protective role, so women may have some protection against disease progression.

Sex differences have been observed both in humans and in animal models used in preclinical studies. However, traditionally most research in mice and rats has not taken these differences into account and has been done only in males.

The few studies on liver fibrosis that have used both sexes have focused on the role of sex hormones in the early stages of its progression, leaving aside liver cirrhosis. Researchers from the Translational Research in Hepatic Diseases Group at IGTP and Germans Trias Hospital, in collaboration with CMCiB and EndosMedicina addressed this research gap in a study published in the journal Laboratory Animals.

Researchers wanted to determine the effect of sex in a model of cirrhosis with ascites in rats that has so far only been described for males. They induced cirrhosis of the liver in animals by repeatedly administering carbon tetrachloride and varying the dose until ascites appeared.

The response of males and females was different. Males developed ascites in the time predicted by the model, whereas females only did so with further increases in dose and twice as long. These results suggest a difference in susceptibility to carbon tetrachloride toxicity and regenerative response.

Sara Capdevila, technical director of CMCiB and co-author of the study, states: "We have observed a significant impact of sex in the model used for studying liver disease. This is a clear example that reducing the number of animals used cannot justify excluding one sex from preclinical studies. Experimental design must always take into account the possibility of differences between both sexes". She adds that "establishing a disease model based on whether it is male or female is essential to adopting a personalised medicine approach and achieving better translation of research from animals to humans".

Thus, the authors stress the importance of continuing to conduct preclinical research also in females. In fact, current recommendations call for gender parity in experiments, and it is hoped that the existing bias will be reduced in the coming years.

As for liver cirrhosis research, Ramon Bartolí, co-leader of IGTP's research group and researcher at Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), points out that "in the future, the dose increase in female models and the role of sex hormones in the observed differences should be properly evaluated. Specific studies should determine whether males and females show comparable results in relation to toxicity mortality rates, incidence and time to development of ascites in our modified model".