Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury
Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a reasonable hypothesis would be that an underlying ch...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2018-01-01
|
| Series: | Journal of Immunotoxicology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/1547691X.2018.1467982 |
| _version_ | 1818252379278016512 |
|---|---|
| author | Alastair Mak Tiffany Cho Jack Uetrecht |
| author_facet | Alastair Mak Tiffany Cho Jack Uetrecht |
| author_sort | Alastair Mak |
| collection | DOAJ |
| description | Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a reasonable hypothesis would be that an underlying chronic liver disease such as non-alcoholic steatohepatitis (NASH) would increase the risk of developing IDILI due to inflammation and release of danger signals from damaged cells. In order to test this hypothesis, mice were fed a methionine-/choline-deficient (MCD) diet that produces a consistent NASH phenotype, along with amodiaquine (AQ) – a drug known to cause IDILI in humans. This study employed both wild-type C57BL/6 mice and PD-1−/− mice co-treated with anti-CTLA-4 antibodies. The PD-1−/− + anti-CTLA-4 model produces an immune-mediated liver injury very similar to the idiosyncratic liver injury observed in humans. The liver injury observed in the present experiment was dominated by the injury caused by the MCD diet; there was no significant difference between mice treated with the MCD diet alone and those also treated with AQ, whether in wild-type mice of the PD-1−/− model. Therefore, the MCD diet, which results in a state that mimics NASH, did not appear to increase the liver injury associated with AQ treatment. Ultimately, an animal model is just that – only a model, and cannot provide a definitive answer to clinical questions. However, given the difficulty of performing clinical studies with appropriate control populations, the present results provide important evidence to support a general clinical finding that underlying liver injury does not usually increase the risk of IDILI. |
| first_indexed | 2024-12-12T16:23:14Z |
| format | Article |
| id | doaj.art-d4d477435e8745668c09676398d858d4 |
| institution | Directory Open Access Journal |
| issn | 1547-691X 1547-6901 |
| language | English |
| last_indexed | 2024-12-12T16:23:14Z |
| publishDate | 2018-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Immunotoxicology |
| spelling | doaj.art-d4d477435e8745668c09676398d858d42022-12-22T00:18:57ZengTaylor & Francis GroupJournal of Immunotoxicology1547-691X1547-69012018-01-01151909510.1080/1547691X.2018.14679821467982Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injuryAlastair Mak0Tiffany Cho1Jack Uetrecht2University of TorontoUniversity of TorontoUniversity of TorontoClinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a reasonable hypothesis would be that an underlying chronic liver disease such as non-alcoholic steatohepatitis (NASH) would increase the risk of developing IDILI due to inflammation and release of danger signals from damaged cells. In order to test this hypothesis, mice were fed a methionine-/choline-deficient (MCD) diet that produces a consistent NASH phenotype, along with amodiaquine (AQ) – a drug known to cause IDILI in humans. This study employed both wild-type C57BL/6 mice and PD-1−/− mice co-treated with anti-CTLA-4 antibodies. The PD-1−/− + anti-CTLA-4 model produces an immune-mediated liver injury very similar to the idiosyncratic liver injury observed in humans. The liver injury observed in the present experiment was dominated by the injury caused by the MCD diet; there was no significant difference between mice treated with the MCD diet alone and those also treated with AQ, whether in wild-type mice of the PD-1−/− model. Therefore, the MCD diet, which results in a state that mimics NASH, did not appear to increase the liver injury associated with AQ treatment. Ultimately, an animal model is just that – only a model, and cannot provide a definitive answer to clinical questions. However, given the difficulty of performing clinical studies with appropriate control populations, the present results provide important evidence to support a general clinical finding that underlying liver injury does not usually increase the risk of IDILI.http://dx.doi.org/10.1080/1547691X.2018.1467982Idiosyncratic drug-induced liver injurynon-alcoholic steatohepatitisanimal model |
| spellingShingle | Alastair Mak Tiffany Cho Jack Uetrecht Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury Journal of Immunotoxicology Idiosyncratic drug-induced liver injury non-alcoholic steatohepatitis animal model |
| title | Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury |
| title_full | Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury |
| title_fullStr | Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury |
| title_full_unstemmed | Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury |
| title_short | Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury |
| title_sort | use of an animal model to test whether non alcoholic fatty liver disease increases the risk of idiosyncratic drug induced liver injury |
| topic | Idiosyncratic drug-induced liver injury non-alcoholic steatohepatitis animal model |
| url | http://dx.doi.org/10.1080/1547691X.2018.1467982 |
| work_keys_str_mv | AT alastairmak useofananimalmodeltotestwhethernonalcoholicfattyliverdiseaseincreasestheriskofidiosyncraticdruginducedliverinjury AT tiffanycho useofananimalmodeltotestwhethernonalcoholicfattyliverdiseaseincreasestheriskofidiosyncraticdruginducedliverinjury AT jackuetrecht useofananimalmodeltotestwhethernonalcoholicfattyliverdiseaseincreasestheriskofidiosyncraticdruginducedliverinjury |