Mycophenolate Mofetil Hepatotoxicity Associated With Mitochondrial Abnormality in Liver Transplant Recipients and Mice.
J Pediatr Gastroenterol Nutr
; 73(4): 463-470, 2021 10 01.
Article
em En
| MEDLINE
| ID: mdl-34016874
ABSTRACT
OBJECTIVES:
Mycophenolate mofetil (MMF) is a widely used immunosuppressive agent. MMF hepatotoxicity has been reported in non-transplant and renal transplant patients with minimal histologic description. This is the first study describing detailed histology and ultrastructure of MMF hepatotoxicity.METHODS:
Four liver-transplant recipients (Cases 1-4) were suspected to have MMF hepatotoxicity. Cases 1-3 (two females and one male; 4-17âyears) had multiple biopsies for liver function test (LFT) abnormalities. Case 4 (female; 16âyears) had a surveillance biopsy. Electron-microscopic examination (EM) was requested on Cases 1-3 for unexplained, persistent LFT elevation and histologic abnormalities despite therapy and Case 4 for unexplained histologic abnormalities despite a stable clinical course. To confirm the pathologic changes in the human allografts, livers from MMF-treated and untreated mice were also reviewed.RESULTS:
While the allograft biopsies showed nonspecific histologic changes, EM revealed unequivocal mitochondrial abnormalities similar to those seen in primary and secondary mitochondrial disorders. In Cases 1 and 2, LFTs improved after stopping and reducing MMF, respectively. In Case 3, pre- and post-MMF treatment biopsies were performed and only the post-MMF biopsy demonstrated mitochondrial abnormalities. Mitochondrial abnormality in Case 4 was subclinical. The mouse study confirmed that MMF caused various stress changes in the mitochondria; number of mitochondria/cell (mean ± standard deviation; untreated group 58.25â±â8.426; MMF-treated group 76.37â±â18.66), number of lipid droplets/cell (untreated 0.9691â±â1.150; MMF-treated 3.649â±â4.143) and sizes of mitochondria (µm, untreated 0.8550â±â0.3409; MMF-treated 0.9598â±â0.5312) were significantly increased in hepatocytes in the MMF-treated mice compared with the untreated mice (Pâ<â0.0001).CONCLUSIONS:
Although MMF is safe for the majority of patients, MMF can cause mitochondrial stress, which may trigger more severe mitochondrial abnormalities in a small subset. MMF hepatotoxicity should be considered for MMF-treated patients with unexplained, persistent LFT abnormalities and nonspecific histologic findings. EM should be requested for these cases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transplante de Fígado
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Doença Hepática Induzida por Substâncias e Drogas
/
Imunossupressores
/
Ácido Micofenólico
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Animals
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Female
/
Humans
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Male
Idioma:
En
Revista:
J Pediatr Gastroenterol Nutr
Ano de publicação:
2021
Tipo de documento:
Article