xenobiotic induced liver pathology
TRANSCRIPT
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Xenobiotic-Induced Toxicologic Pathology of the Liver
R. R. [email protected]
Photomicrographs courtesy of the National Toxicology Program (http://ntp.niehs.nih.gov)
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Sorting Out the Process
Non-neoplasticPutative preneoplasticNeoplastic
Exacerbation of background lesionsAging changesSpecies & strain specificityXenobiotic specificity
Temporal relationshipsAcutePrechronicIntermediateChronic
Specific hepatic changes often do not occur in isolation
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Outline
• Cytologic Alteration• Degeneration• Vascular Changes• Cell Death/Necrosis• Inflammation
• Proliferative Lesions• Neoplastic Lesions• Controversial Lesions
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Cytologic Alteration•Clear cell change•Enzyme induction•Peroxisome proliferation•Fatty change•Cholestasis•Atrophy
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Clear cell change - Glycogen accumulation
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Normal glycogen accumulation Glycogen depletion
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Enzyme Induction
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Constitutive Enzyme Activity
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Enzyme Induction
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Increased Smooth Endoplasmic Reticulum
Control Treated
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Persistent & Excessive Enzyme Induction
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Persistent & Excessive Enzyme Induction
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Peroxisome Proliferation
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Control Treated
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Peroxisome Proliferation Ultrastructure
Control Treated
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Peroxisome Proliferators
• Hypolipidemics– Clofibrate– Gemfibrozil
• Methaphenilene• Ibuprofen• Diethylhexyl phthalate
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Macrovesicular Fatty Change
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Microvesicular Fatty Change
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Cholestasis
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Atrophy
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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
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Degeneration
•Cystic degeneration•Biliary cysts•Pigments•Inclusions
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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
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Biliary Cysts
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Pigment Deposition
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Pigment Deposition
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Hyaline Degeneration(Inclusions)
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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
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Vascular Ectasia
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Cell Death
•Single cell•Apoptosis
•Focal necrosis•Patchy necrosis•Zonal necrosis
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Single Cell Necrosis & Apoptosis
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Focal Necrosis and Inflammation
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Focal Necrosis and Inflammation
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Teutsch, et al. 1999. Hepatology 29:494-505
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Teutsch, et al. 1999. Hepatology 29:494-505
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Teutsch, et al. 1999. Hepatology 29:494-505
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Teutsch, et al. 1999. Hepatology 29:494-505
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Inflammation
• Spontaneous– Acute, chronic, focal, diffuse
• Hepatocellular• Biliary
• Xeniobiotic-induced– Acute, chronic, focal, diffuse
• Hepatocellular• Biliary
• Cirrhosis• Cholangiofibrosis
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Focal Inflammation
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Chronic Active Inflammation
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Bile Duct Hyperplasia and Inflammation
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Proliferative LesionsHepatocellular Lesions• Foci of cellular alteration• Hyperplasias
– Regenerative hyperplasia– Focal hyperplasia
• Hepatocellular adenoma• Hepatocellular carcinoma• Hepatoblastoma
Biliary Lesions• Cholangioma• CholangiocarcinomaCombined Lesions• Hepatocholangioma• HepatocholangiocarcinomaQuestionable Lesions• Cholangiofibrosis vs.
“Cholangiocarcinoma”• Ito cell “proliferations”
Oval Cell Lesions• Oval cell hyperplasia• Oval cell neoplasia
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Proliferative LesionsHepatocellular Lesions• Foci of cellular alteration• Hyperplasias
– Regenerative hyperplasia– Focal hyperplasia
• Hepatocellular adenoma• Hepatocellular carcinoma• Hepatoblastoma
Biliary Lesions• Cholangioma• CholangiocarcinomaCombined Lesions• Hepatocholangioma• HepatocholangiocarcinomaQuestionable Lesions• Cholangiofibrosis vs.
“Cholangiocarcinoma”• Ito cell “proliferations”
Oval Cell Lesions• Oval cell hyperplasia• Oval cell neoplasia
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Foci of Cellular Alteration
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Foci of cellular alteration occur spontaneously in older rodents and when induced by treatment may occur in younger rodents.
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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)
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Proliferative LesionsHepatocellular Lesions• Foci of cellular alteration• Hyperplasias
– Regenerative hyperplasia– Focal hyperplasia
• Hepatocellular adenoma• Hepatocellular carcinoma• Hepatoblastoma
Biliary Lesions• Cholangioma• CholangiocarcinomaCombined Lesions• Hepatocholangioma• HepatocholangiocarcinomaQuestionable Lesions• Cholangiofibrosis vs.
“Cholangiocarcinoma”• Ito cell “proliferations”
Oval Cell Lesions• Oval cell hyperplasia• Oval cell neoplasia
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Regenerative Hyperplasia; Nodular hyperplasia
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Liver plates merge with surrounding hepatocytes but have a mild compression
Slightly Enlarged Hepatocytes without Phenotypical Alteration
Harada (2008) NTP Satellite Symposium
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Portal triads
C.V.
Harada (2008) NTP Satellite Symposium
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Portal triads
Harada (2008) NTP Satellite Symposium
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Another Similar Lesion Located Beneaththe Hepatic Capsule
Harada (2008) NTP Satellite Symposium
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Proliferative LesionsHepatocellular Lesions• Foci of cellular alteration• Hyperplasias
– Regenerative hyperplasia– Focal hyperplasia
• Hepatocellular adenoma• Hepatocellular carcinoma• Hepatoblastoma
Biliary Lesions• Cholangioma• CholangiocarcinomaCombined Lesions• Hepatocholangioma• HepatocholangiocarcinomaQuestionable Lesions• Cholangiofibrosis vs.
“Cholangiocarcinoma”• Ito cell “proliferations”
Oval Cell Lesions• Oval cell hyperplasia• Oval cell neoplasia
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Hepatocellular Adenoma
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Carcinoma Arising in Adenoma
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Hepatocellular Carcinoma
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Hepatocellular Carcinoma
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Hepatoblastoma
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Proliferative LesionsHepatocellular Lesions• Foci of cellular alteration• Hyperplasias
– Regenerative hyperplasia– Focal hyperplasia
• Hepatocellular adenoma• Hepatocellular carcinoma• Hepatoblastoma
Biliary Lesions• Cholangioma• CholangiocarcinomaCombined Lesions• Hepatocholangioma• HepatocholangiocarcinomaQuestionable Lesions• Cholangiofibrosis vs.
“Cholangiocarcinoma”• Ito cell “proliferations”
Oval Cell Lesions• Oval cell hyperplasia• Oval cell neoplasia
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Oval Cell Hyperplasia
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Proliferative LesionsHepatocellular Lesions• Foci of cellular alteration• Hyperplasias
– Regenerative hyperplasia– Focal hyperplasia
• Hepatocellular adenoma• Hepatocellular carcinoma• Hepatoblastoma
Biliary Lesions• Cholangioma• CholangiocarcinomaCombined Lesions• Hepatocholangioma• HepatocholangiocarcinomaQuestionable Lesions• Cholangiofibrosis vs.
“Cholangiocarcinoma”• Ito cell “proliferations”
Oval Cell Lesions• Oval cell hyperplasia• Oval cell neoplasia
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Cholangioma
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Cholangiocarcinoma
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Hepatocholangioma
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Hepatocholangiocarcinoma
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Controversial Proliferative Lesions
• Cholangiofibrosis vs. cholangiocarcinoma• Ito cell hyperplasia vs. Ito cell tumor
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Cholangiofibrosis vs. Cholangiocarcinoma
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Cholangiofibrosis
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Cholangiofibrosis
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Cholangiofibrosis
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Cholangiofibrosis vs. Cholangiocarcinoma
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Cholangiofibrosis Cholangiocarcinoma
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Ito Cell Tumor
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Ito Cell “Tumor”
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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