*3.1.3 Genetic models*

Genetically modified animals, by insertion, modification, or deletion of certain DNA sequences, have been widely used for the study of NAFLD and new drug discovery. Genetic models used to study this pathological condition include the following:


5 weeks of age, and by 14 weeks of age, their body composition is over 40 percent lipid. Many metabolic syndrome features, such as hyperphagia, hyperglycemia, hyperinsulinemia, hypercholesterolemia, adipocyte hypertrophy, hyperplasia, and muscle atrophy, can also be observed in this animal model. The presence of an excess in adipocyte mass in these rats, along with insulin resistance, leads to *de novo* lipogenesis and an increased release of free fatty acids up taken by hepatic cells, leading to moderate hepatic steatosis. There is also documented presence of pro-inflammation markers such as TNF-alpha, IL-1beta, and IL-6. This model is more often employed to research inflammation and liver steatosis as associated with obesity [37, 50, 51].


#### **3.2 Models of cirrhosis and hepatocellular carcinoma**

The main complication of CLD is cirrhosis [82]. Liver cirrhosis is a chronic, diffuse, and irreversible liver disease characterized by the existence of fibrosis, portal hypertension, and regenerative nodules. As a consequence, there are fewer liver cells and the liver stops carrying out its usual functions, including the synthesis of proteins (especially those that act in blood coagulation), the production of bile, the neutralization and elimination of foreign substances from the body, and the production of defenses against infection [83]. Although their clinical, biological, and laboratory manifestations can often suggest what the diagnosis is, this can only be confirmed *via* morphological study (biopsy). The prognosis is poor, and patients die from gastrointestinal bleeding, hepatocellular failure, neoplastic degeneration, or metastasis [84].

The development of hepatocellular carcinoma is common in the evolution of patients with liver cirrhosis [85]. Once cirrhosis is diagnosed, the chance of developing hepatocellular carcinoma is of 20% during the following 5 years. Since this type of carcinoma is frequently derived from cirrhosis, its clinical manifestations are often codependent. Prognosis depends on the evolution of cirrhosis at the time the cancer is

### *Models of Hepatotoxicity for the Study of Chronic Liver Disease DOI: http://dx.doi.org/10.5772/intechopen.106219*

diagnosed. If hepatic functional reserve is good and hepatocellular carcinoma is asymptomatic, the patient may survive for several years. If the cirrhosis is very advanced and the carcinoma is very developed, the patient will die in a matter of weeks [86].

Chemically induced animal models are most often used for the study of cirrhosis and hepatocellular carcinoma, and some have already been mentioned above. However, to achieve the development of cirrhosis, portal hypertension, or liver cancer, it is necessary to extend the exposure time to the toxic agent, and there are other models specifically focused on the development of liver cirrhosis or hepatocellular carcinoma (**Figure 2**).
