Liver diseases
The term liver disease encapsulates over 100 different types of pathologies, which together affect at least 2 million people in the UK. Liver disease is the third leading cause of premature death in the UK. Liver disease and liver cancer together caused 2.5% of deaths in England in 2020. On average, 40 people die from liver disease every day in the country.
Despite being 90% preventable, liver diseases have been on the rise for the last few decades. Since 1970, deaths due to liver disease have increased by 400%, in contrast with other major diseases, such as heart disease and cancer, where deaths have either remained stable or decreased.
Understanding the liver
The liver is the second largest organ in the body and is just as vital an organ as the heart. It works hard, performing hundreds of complex functions. These include:
- Processing and breaking down digested food
- fighting infections and illness
- removing toxins (poisons), such as alcohol, from the body
- controlling cholesterol levels
- helping blood clot
- releasing bile, a liquid that breaks down fats and aids digestion
Common liver diseases
This means that a number of different things can go wrong with the liver, most of which don’t even cause obvious signs or symptoms until the disease is fairly advanced and the liver is damaged. Here are some common liver diseases :
Alcohol-related liver diseases
Excessive alcohol consumption over multiple years damages the liver and can lead to scarring of the liver, also known as cirrhosis. Alcohol-related liver disease accounts for 60% of all liver disease.
Non-alcoholic fatty liver disease
Fat builds up within liver cells, usually in overweight or obese people, and damages them. 63% of UK adults are now classed as obese and overweight, and an estimated 1 in 3 have early-stage non-alcohol related fatty liver disease (NAFLD). Losing 10% of body weight is usually enough to improve liver function in those with NAFLD. Experts predict that over the next decade, NAFLD will become the leading cause of endstage liver disease and transplantation.
Hepatitis
A viral infection or the exposure to harmful substances such as alcohol can cause inflammation or swelling of the liver. 180,000 people are chronically infected with hepatitis B and 143,000 are estimated to carry the hepatitis C virus.
Liver cancer
Liver cancer is the fastest rising cause of cancer death in the UK, with only 13% of patients surviving past 5 years. Around 6,000 cases of primary liver cancer are diagnosed each year in the UK, which means almost 16 people per day get the bad news. The vast majority of them will have underlying advanced liver disease.
Haemochromatosis
A genetic disorder that causes the gradual build-up of iron in the body, usually around the liver
Primary biliary cirrhosis
A rare, long-term type of liver disease that damages the bile ducts in the liver
Animal models of liver disease
Considering the high prevalence of liver disease worldwide, and the lack of preclinical alternatives, animal models are crucial to understand the human pathogenesis of liver disease, identifying therapeutic targets, potential drug and biomarkers, and testing novel medication. Further elucidating the progression of alcohol-related (AFLD) and non-alcoholic fatty liver disease (NAFLD) but also alcohol-related (ASH) and non-alcoholic (NASH) steatohepatitis, to advanced chronic liver disease (ACLD) notably will help a great number of patients.
To reflect this diversity, researchers have engineered just as many animal models to represent the spectrum of symptoms. We can only summarise here the most widely used experimental models of chronic liver disease, starting from early stages of fatty liver disease (non-alcoholic and alcoholic) to steatohepatitis, advanced cirrhosis and end-stage primary liver cancer.
Alcohol related liver disease
To model alcohol related liver disease, animals can simply be given alcohol in their water of food. But it isn’t always easy to reproduce the human disease. To date, none of the current preclinical animal models reproduce all of the major features of the human conditions, mostly due to animal's aversion to alcohol. There isn’t a single animal model for alcohol related liver disease.
Indeed, rodents aren’t that similar to humans when it comes to alcohol consumption. They have a natural aversion to alcohol and their rate of alcohol catabolism is up to 5 times faster than humans. Their metabolic rate is also naturally faster and they don’t naturally develop an addictive behavior. Rodents will stop consuming alcohol when blood acetaldehyde levels increase. This, together with other factors, means that rodents usually get relatively mild hepatic damage and tend to maintain a high blood alcohol concentration (BAC), compared to humans.
That said, current animal models remain a very useful tool to study blood alcohol concentration and alcohol related conditions and understand key pathophysiological events such as steatosis and inflammation.
Steatosis (both alcohol-related and non-alcoholic)
Steatosis, also called fatty liver disease is a common condition caused by having too much fat (lipids) build up within cells or organs, in this case the liver. This can be linked to a high fat diet and/or alcohol consumption.
Animal models have been developed to include both those factors, and indeed a combination of alcohol in the drinking water with high-fat diets have led to enhanced liver inflammation and injury in rodents, with synergistic effects on fibrosis development. Researchers have come up with different ways of feeding the rodents to overcome their gustatory aversion to alcohol, notably the Lieber-DeCarli diet, a unique liquid diet procedure created over 25 years ago by Charles Lieber.
Depending on the scientific question or the rodent's species, strain and gender the duration of the feeding but also the content of the diet can be modified to fit the progression of liver damage. Surgical gastric implants were engineered in 1984 to overcome the limitations of the liquid diet and induce later stages of the disease in rodents. This model (Tsukamoto-French model) is really valuable because the investigator has complete control of ethanol intake and diet, as well as administration rate and mode of delivery. The application of this model leads to pathologic changes which resemble human alcohol-related liver disease.
Non-alcoholic fatty liver disease (NAFLD)
Non alcoholic fatty liver disease (NAFLD) can be induced in animals with a special diet, sometimes combined with a proinflammatory hit, which can vary in content and length depending on which stages of the disease are of interest. Their pathophysiology ranges from simple steatosis to advanced liver fibrosis. Animal models that mirror the pathophysiology of every stage of human NAFLD progression provide important insights into disease pathogenesis, guiding the development of much needed therapeutic option.
This also means that researchers studying NAFLD need to have a very clear understanding of which pathological event they aim to study in order to choose the animal model that best suits their research goals.
For example, the Methionine- and choline-deficient diet will replicate part of the histological phenotype typical of human NASH in a relatively short period but does not replicate the NAFLD- related metabolic syndrome, with poor concordance between differentially expressed genes in this model and human NASH. Thus the uses of this MCD model is limited by the disparity in metabolic changes observed between the model and the vast majority of human patients with NAFLD. A choline-deficient L-amino-defined diet, on the other hand, will take longer to develop but fibrosis develops further with possible hepatic tumors. They can be used to study the progression from NAFLD to NASH and further to hepatocellular carcinomas.
There are a number of different diets with or without chemical inputs that produce a range of symptoms in rodents that mimic what happens in humans.
Advanced chronic liver disease
Regardless of the varying causes of chronic liver disease, the progression of the disease converges in cirrhosis that may even progress to cancerous lesions. Despite the increased research efforts over the last few years to find an effective treatment for advanced chronic liver disease, liver transplantation currently remains the only therapeutic option. There is still a long path of preclinical research before new therapeutic options reach the bedside. For this reason, it is essential to have well-characterized animal models that closely mirror the specific aspects of advanced chronic liver disease.
The most widely used animal models of cirrhosis worldwide, derive from chronic exposure of rodents to hepato-toxins. This causes fibrosis, and other clinical complications observed in patients. Other types of model exists (such as surgical models), as well as models of specific aetiologies of cirrhosis.
Primary liver cancer
Liver cancer can lead to advanced chronic liver disease and vice versa. In the last few years a number of in vivo models of the main primary liver cancers have been developed. Researchers look for animal models that are immunocompetent and/or developed in a host with a species-matched microenvironment, with a full immune response. Ideally they should also have fast developing tumours that recapitulate the genetic, anatomic, and phenotypic features that are found in human cancers.
A variety of strategies have been used to generate primary liver cancer in rodents. These include genetic modifications such as expression of oncogenes, disruption of single or multiple tumour suppressor genes or stem cell transduction, but also chemotoxic injections and xenotransplantations.
Organoid models
Although animal models are still the best approach to comprehensively study the pathophysiology of liver diseases and to develop new drugs, sometimes translating the findings from animals to humans can be challenging.
3D human cell cultures have been developed to complement animal studies. These organoids remove the confounding variables that might be introduced by animal models and are more complex than homogenized cell cultures. They allow researchers to study specific cellular functions and regulation, as well as drug efficacy and toxicity, in a liver-centered environment. They have already been applied in the context of NAFLD/NASH studies.
Animal welfare
Many countries regulate animal welfare by law and demand that the severity of animal experiments are evaluated and considered when performing biomedical research. The welfare of the animals must be considered alongside the scientific questions, especially when researchers have no choice between different animal models.
When pursuing animal experiments, scientists have to balance two goals: animal welfare and the potential benefit of research. As such they try to choose animal models that answer the scientific reasoning with the least possible distress on the animals.
Treatments for liver disease
Most of the time, liver disease can be reversed with lifestyle modifications such as changes in diet and alcohol consumption. However, when the disease progresses, medical assistance might be required.
Treatment for liver disease depends on the type of liver disease and how far it has progressed. However, there are currently no medications approved for NAFLD, though some are in clinical trials. Various medicines can be used to manage the problems associated with the condition, such as medicine to treat high blood pressure, treat high cholesterol, treat type 2 diabetes and treat obesity. Liver failure may ultimately require a liver transplant.
As liver disease affects more and more people, it is important that research continues to ultimately better understand the variety of conditions that affect the liver and find new ways to treat them.
Last edited: 25 January 2023 13:33