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Review
. 2013 May;58(5):1415-21.
doi: 10.1007/s10620-012-2493-9. Epub 2012 Dec 5.

Clinical and histological features of idiosyncratic acute liver injury caused by temozolomide

Lafaine M Grant  1 , David E Kleiner, Hari S Conjeevaram, Raj Vuppalanchi, William M Lee
Affiliations
Review

Clinical and histological features of idiosyncratic acute liver injury caused by temozolomide

Lafaine M Grant et al. Dig Dis Sci. 2013 May.

Abstract

Objective: To describe the clinical, biochemical and histological features of 4 patients with apparent hepatotoxicity due to temozolomide and to summarize the available literature of hepatotoxicity associated with this agent.

Design: Case series

Setting: Patients were participants in the Drug-Induced Liver Injury Network a United States multicenter cooperative study.

Patients: Four patients (ages 47 to 70 years; 3 men, 1 woman) developed liver injury 1 to 7 months after starting temozolomide chemotherapy.

Intervention: Discontinuation of temozolomide therapy.

Results: Among the first 1000 cases of drug-induced liver injury enrolled in a prospective U.S. multicenter database, 4 cases of temozolomide hepatotoxicity were identified (0.5%).Three were jaundiced and the initial pattern of serum enzyme elevations was often hepatocellular or mixed, but usually became cholestatic with time. Immunoallergic and autoimmune features were absent. Liver biopsies showed varying degrees of cholestasis, mild inflammation, focal hepatocellular injury and prominent bile duct damage or paucity. The liver injury tended to be prolonged and 3 patients still had liver tests abnormalities (one with jaundice) when they died of brain tumor or complications of its therapy 1 to 18 months later.

Conclusion: Temozolomide hepatotoxicity although infrequent, can necessitate interruption of cancer chemotherapy and cause significant debility in already compromised patients.

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Figures

Figure 1
Figure 1
Representative pathologic changes in temozolomide hepatotoxicity. Case 1 (A-C). A: Portal area with mild inflammation. No duct is seen. (H&E, 400x) B: (106-0028) Zone 3 cholestasis (arrows) with mild inflammation. (H&E, 600x) C: (106-0028) Cytokeratin 7 staining highlights periportal hepatocytes as well as the bile ducts in this portal area. (CK7, 200x). Case 2 (D only). Marked interface hepatitis with eosinophils and duct injury (arrow) (H&E, 400x). Case 3 (E only). Zone 3 cholestasis, most evident in canaliculi (arrows). Foamy macrophages (Mac) are seen in one corner. (H&E, 600x).
Figure 1
Figure 1
Representative pathologic changes in temozolomide hepatotoxicity. Case 1 (A-C). A: Portal area with mild inflammation. No duct is seen. (H&E, 400x) B: (106-0028) Zone 3 cholestasis (arrows) with mild inflammation. (H&E, 600x) C: (106-0028) Cytokeratin 7 staining highlights periportal hepatocytes as well as the bile ducts in this portal area. (CK7, 200x). Case 2 (D only). Marked interface hepatitis with eosinophils and duct injury (arrow) (H&E, 400x). Case 3 (E only). Zone 3 cholestasis, most evident in canaliculi (arrows). Foamy macrophages (Mac) are seen in one corner. (H&E, 600x).
Figure 1
Figure 1
Representative pathologic changes in temozolomide hepatotoxicity. Case 1 (A-C). A: Portal area with mild inflammation. No duct is seen. (H&E, 400x) B: (106-0028) Zone 3 cholestasis (arrows) with mild inflammation. (H&E, 600x) C: (106-0028) Cytokeratin 7 staining highlights periportal hepatocytes as well as the bile ducts in this portal area. (CK7, 200x). Case 2 (D only). Marked interface hepatitis with eosinophils and duct injury (arrow) (H&E, 400x). Case 3 (E only). Zone 3 cholestasis, most evident in canaliculi (arrows). Foamy macrophages (Mac) are seen in one corner. (H&E, 600x).
Figure 1
Figure 1
Representative pathologic changes in temozolomide hepatotoxicity. Case 1 (A-C). A: Portal area with mild inflammation. No duct is seen. (H&E, 400x) B: (106-0028) Zone 3 cholestasis (arrows) with mild inflammation. (H&E, 600x) C: (106-0028) Cytokeratin 7 staining highlights periportal hepatocytes as well as the bile ducts in this portal area. (CK7, 200x). Case 2 (D only). Marked interface hepatitis with eosinophils and duct injury (arrow) (H&E, 400x). Case 3 (E only). Zone 3 cholestasis, most evident in canaliculi (arrows). Foamy macrophages (Mac) are seen in one corner. (H&E, 600x).
Figure 1
Figure 1
Representative pathologic changes in temozolomide hepatotoxicity. Case 1 (A-C). A: Portal area with mild inflammation. No duct is seen. (H&E, 400x) B: (106-0028) Zone 3 cholestasis (arrows) with mild inflammation. (H&E, 600x) C: (106-0028) Cytokeratin 7 staining highlights periportal hepatocytes as well as the bile ducts in this portal area. (CK7, 200x). Case 2 (D only). Marked interface hepatitis with eosinophils and duct injury (arrow) (H&E, 400x). Case 3 (E only). Zone 3 cholestasis, most evident in canaliculi (arrows). Foamy macrophages (Mac) are seen in one corner. (H&E, 600x).
Figure 2
Figure 2
Biochemical profile over the course of liver injury and in relationship to drug administration and withdrawal. Liver biochemistries include alanine aminotransferase (ALT) and alkaline phosphatase (Alk P).
Figure 2
Figure 2
Biochemical profile over the course of liver injury and in relationship to drug administration and withdrawal. Liver biochemistries include alanine aminotransferase (ALT) and alkaline phosphatase (Alk P).
Figure 2
Figure 2
Biochemical profile over the course of liver injury and in relationship to drug administration and withdrawal. Liver biochemistries include alanine aminotransferase (ALT) and alkaline phosphatase (Alk P).
Figure 2
Figure 2
Biochemical profile over the course of liver injury and in relationship to drug administration and withdrawal. Liver biochemistries include alanine aminotransferase (ALT) and alkaline phosphatase (Alk P).
See this image and copyright information in PMC

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