Examples of chemical and drug-induced liver lesions including non-neoplastic and neoplastic proliferative changes typical found in prechronic and chronic rat and mouse toxicity studies are provided with photomicrograph examples.

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Xenobiotic-Induced Liver Pathology

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Index of Slides

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
8. Constitutive Enzyme Activity
9. Enzyme Induction
10. Increased Smooth Endoplasmic Reticulum Control Treated
11. Persistent & Excessive Enzyme Induction
12. Persistent & Excessive Enzyme Induction
13. Peroxisome Proliferation
14. Control Treated
15. Peroxisome Proliferation Ultrastructure Control Treated
16. Peroxisome Proliferators • Hypolipidemics – Clofibrate – Gemfibrozil • Methaphenilene • Ibuprofen • Diethylhexyl phthalate
17. Macrovesicular Fatty Change
18. Microvesicular Fatty Change
19. Cholestasis
20. Atrophy
21. 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
22. Degeneration •Cystic degeneration •Biliary cysts •Pigments •Inclusions
23. 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
24. Biliary Cysts
25. Pigment Deposition
26. Pigment Deposition
27. Hyaline Degeneration (Inclusions)
28. 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
29. Vascular Ectasia
30. Cell Death •Single cell •Apoptosis •Focal necrosis •Patchy necrosis •Zonal necrosis
31. Single Cell Necrosis & Apoptosis
32. Focal Necrosis and Inflammation
33. Focal Necrosis and Inflammation
34. Teutsch, et al. 1999. Hepatology 29:494-505
35. Teutsch, et al. 1999. Hepatology 29:494-505
36. Teutsch, et al. 1999. Hepatology 29:494-505
37. Teutsch, et al. 1999. Hepatology 29:494-505
38. Inflammation • Spontaneous – Acute, chronic, focal, diffuse • Hepatocellular • Biliary • Xeniobiotic-induced – Acute, chronic, focal, diffuse • Hepatocellular • Biliary • Cirrhosis • Cholangiofibrosis
39. Focal Inflammation
40. Chronic Active Inflammation
41. Bile Duct Hyperplasia and Inflammation
42. 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
43. 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
44. Foci of Cellular Alteration
45. Foci of cellular alteration occur spontaneously in older rodents and when induced by treatment may occur in younger rodents.
46. 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)
47. 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
48. Regenerative Hyperplasia; Nodular hyperplasia
49. Liver plates merge with surrounding hepatocytes but have a mild compression Slightly Enlarged Hepatocytes without Phenotypical Alteration Harada (2008) NTP Satellite Symposium
50. Portal triads C.V. Harada (2008) NTP Satellite Symposium
51. Portal triads Harada (2008) NTP Satellite Symposium
52. Another Similar Lesion Located Beneath the Hepatic Capsule Harada (2008) NTP Satellite Symposium
53. 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
54. Hepatocellular Adenoma
55. Carcinoma Arising in Adenoma
56. Hepatocellular Carcinoma
57. Hepatocellular Carcinoma
58. Hepatoblastoma
59. 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
60. Oval Cell Hyperplasia
61. 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
62. Cholangioma
63. Cholangiocarcinoma
64. Hepatocholangioma
65. Hepatocholangiocarcinoma
66. Controversial Proliferative Lesions • Cholangiofibrosis vs. cholangiocarcinoma • Ito cell hyperplasia vs. Ito cell tumor
67. Cholangiofibrosis vs. Cholangiocarcinoma
68. Cholangiofibrosis
69. Cholangiofibrosis
70. Cholangiofibrosis
71. Cholangiofibrosis vs. Cholangiocarcinoma
72. Cholangiofibrosis Cholangiocarcinoma
73. Ito Cell Tumor
74. Ito Cell “Tumor”
75. 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