Xenobiotic induced liver pathology

1. Xenobiotic-Induced Toxicologic Pathology of the Liver R. R. Maronpot maronpot@me.com Photomicrographs courtesy of the National Toxicology Program (http://ntp.niehs.nih.gov)

2. Sorting Out the Process Non-neoplastic Putative preneoplastic Neoplastic Exacerbation of background lesions Aging changes Species & strain specificity Xenobiotic specificity Temporal relationships Acute Prechronic Intermediate Chronic Specific hepatic changes often do not occur in isolation

3. Outline • Cytologic Alteration • Degeneration • Vascular Changes • Cell Death/Necrosis • Inflammation • Proliferative Lesions • Neoplastic Lesions • Controversial Lesions

4. Cytologic Alteration •Clear cell change •Enzyme induction •Peroxisome proliferation •Fatty change •Cholestasis •Atrophy

5. Clear cell change - Glycogen accumulation

6. Normal glycogen accumulation Glycogen depletion

7. Enzyme Induction

10. Constitutive Enzyme Activity

11. Enzyme Induction

13. Increased Smooth Endoplasmic Reticulum Control Treated

14. Persistent & Excessive Enzyme Induction

15. Persistent & Excessive Enzyme Induction

16. Peroxisome Proliferation

17. Control Treated

18. Peroxisome Proliferation Ultrastructure Control Treated

19. Peroxisome Proliferators • Hypolipidemics – Clofibrate – Gemfibrozil • Methaphenilene • Ibuprofen • Diethylhexyl phthalate

20. Macrovesicular Fatty Change

23. Microvesicular Fatty Change

26. Cholestasis

27. Atrophy

30. Some Non-neoplastic Structural Alterations Degenerative Changes • Cystic degeneration (spongiosis hepatis) • Biliary cysts • Pigments • Inclusions Vascular Changes • Peliosis (ectasia) • Sinusoidal dilation • Congestion • Hemorrhage • Endothelial change • Thrombosis

31. Degeneration •Cystic degeneration •Biliary cysts •Pigments •Inclusions

38. Some Non-neoplastic Structural Alterations Degenerative Changes • Cystic degeneration (spongiosis hepatis) • Biliary cysts • Pigments • Inclusions • Fatty change (lipidosis) • Atrophy Vascular Changes • Peliosis (ectasia) • Sinusoidal dilation

39. Biliary Cysts

42. Pigment Deposition

44. Pigment Deposition

46. Hyaline Degeneration (Inclusions)

51. Some Non-neoplastic Structural Alterations Degenerative Changes • Cystic degeneration (spongiosis hepatis) • Biliary cysts • Pigments • Inclusions Vascular Changes • Vascular ectasia • Sinusoidal dilation • Hemorrhage • Endothelial change • Thrombosis

52. Vascular Ectasia

57. Cell Death •Single cell •Apoptosis •Focal necrosis •Patchy necrosis •Zonal necrosis

58. Single Cell Necrosis & Apoptosis

59. Focal Necrosis and Inflammation

60. Focal Necrosis and Inflammation

68. Teutsch, et al. 1999. Hepatology 29:494-505

72. Inflammation • Spontaneous – Acute, chronic, focal, diffuse • Hepatocellular • Biliary • Xeniobiotic-induced – Acute, chronic, focal, diffuse • Hepatocellular • Biliary • Cirrhosis • Cholangiofibrosis

73. Focal Inflammation

78. Chronic Active Inflammation

81. Bile Duct Hyperplasia and Inflammation

87. Proliferative Lesions Hepatocellular Lesions • Foci of cellular alteration • Hyperplasias – Regenerative hyperplasia – Focal hyperplasia • Hepatocellular adenoma • Hepatocellular carcinoma • Hepatoblastoma Biliary Lesions • Cholangioma • Cholangiocarcinoma Combined Lesions • Hepatocholangioma • Hepatocholangiocarcinoma Questionable Lesions • Cholangiofibrosis vs. “Cholangiocarcinoma” • Ito cell “proliferations” Oval Cell Lesions • Oval cell hyperplasia • Oval cell neoplasia

89. Foci of Cellular Alteration

95. Foci of cellular alteration occur spontaneously in older rodents and when induced by treatment may occur in younger rodents.

96. Relationship of Foci and Liver Tumors in F344 Rat 2-Year Bioassays • Liver tumor negative studies – No increased incidence of foci at study termination • Liver tumor positive studies – genotoxic agent – 3 to 10-fold increase in multiple foci – Eosinophilic (3-10X); Clear (2-9X); Mixed (3x); Basophilic (4- 8X) • Liver tumor positive studies – non-genotoxic agent – 2 to 15-fold increase in foci – Eosinophilic (4-15X); Mixed (2-5X)

98. Regenerative Hyperplasia; Nodular hyperplasia

101. Liver plates merge with surrounding hepatocytes but have a mild compression Slightly Enlarged Hepatocytes without Phenotypical Alteration Harada (2008) NTP Satellite Symposium

102. Portal triads C.V. Harada (2008) NTP Satellite Symposium

103. Portal triads Harada (2008) NTP Satellite Symposium

104. Another Similar Lesion Located Beneath the Hepatic Capsule Harada (2008) NTP Satellite Symposium

106. Hepatocellular Adenoma

113. Carcinoma Arising in Adenoma

116. Hepatocellular Carcinoma

117. Hepatocellular Carcinoma

121. Hepatoblastoma

127. Oval Cell Hyperplasia

134. Cholangioma

139. Cholangiocarcinoma

143. Hepatocholangioma

146. Hepatocholangiocarcinoma

150. Controversial Proliferative Lesions • Cholangiofibrosis vs. cholangiocarcinoma • Ito cell hyperplasia vs. Ito cell tumor

151. Cholangiofibrosis vs. Cholangiocarcinoma

153. Cholangiofibrosis

175. Cholangiofibrosis vs. Cholangiocarcinoma

176. Cholangiofibrosis Cholangiocarcinoma

177. Ito Cell Tumor

187. Ito Cell “Tumor”

189. Some Summary Points • Liver has remarkable reserve capacity • Responses can be adaptive or adverse • Adverse effects often occur together • Rat liver has a secondary lobular structure that may explain unusual distribution of lesions • Nodular lesions and aggressive proliferative changes in the liver are not necessarily neoplasms

Xenobiotic induced liver pathology

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