Chapter 20 PART IV: Molecular Pathology of Human Disease Molecular Basis of Liver Disease Companion site for Molecular Pathology Author: William B. Coleman and Gregory J. Tsongalis

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 2 Summary of molecular signaling during liver development in mouse. Abbreviations: FGF—Fibroblast growth factor; BMP—Bone morphogenic protein; AFP—α-fetoprotein; Alb—Albumin; HGF— Hepatocyte growth factor; HNF—Hepatocyte nuclear factor; C/EBPα—CCAAT enhancer binding protein-alpha. FIGURE 20.1

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 3 H&E of developing mouse livers. (A) Several hematopoietic cells (arrow) are seen interspersed among hepatoblasts (arrowhead), which display large nuclei and scanty cytoplasm, in an E14 liver section. (B) Fewer hematopoietic cells (arrow) are observed among the hepatocytes (arrowhead) which begin to show cuboidal morphology and large clear cytoplasm as well as begin to display polarity, in an E17 liver section. (C) Similar cuboidal morphology of hepatocytes (arrowhead) is seen in an E19 mouse liver. FIGURE 20.2

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 4 H&E demonstrating the activation of oval cells or facultative adult liver stem cells in experimental models. (A) Several oval cells with oval shape, smaller size, and higher cytoplasmic to nuclear ratio (arrows) are observed around the portal triad (PT) in rat livers after AAF/PHx. Several intermediate hepatocytes (arrowheads) are evident as these oval cells undergo progressive differentiation. (*) shows normal hepatocytes adjoining the ongoing oval cell activation, expansion, and differentiation. (B) Mouse liver after DDC administration for 2 weeks displays atypical ductular hyperplasia (arrows) equivalent of oval cell activation and adjoining normal hepatocytes (*). FIGURE 20.3

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 5 H&E and TUNEL immunohistochemistry exhibiting apoptotic cell death after Fas- and TNFα-mediated liver injury. (A) H&E shows massive cell death 6 hours after Jo-2 antibody administration. (B) Several TUNEL- positive apoptotic nuclei (arrowheads) are evident in the same liver. (C) H&E shows massive cell death 7 hours after D-Galactosamine/LPS administration in mice. (D) Several TUNEL-positive apoptotic nuclei (arrowhead) are evident in the same liver. FIGURE 20.4

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 6 Molecular basis of nonalcoholic steatohepatitis. Insulin resistance results in decreased insulin-induced inhibition of hormone-sensitive lipase (HSL) activity in adipocytes resulting in high rates of lipolysis and increased plasma free fatty acid (FFA) levels. High plasma FFA levels increase FFA flux to the liver. In myocytes, insulin resistance results in decreased glucose uptake and high plasma glucose and insulin levels. In the liver, hyperinsulinemia activates SREBP-1c, leading to increased transcription of lipogenic genes. High plasma glucose levels simultaneously activate ChREBP, which activates glycolysis and lipogenic genes. SREBP-1c and ChREBP ct synergistically to convert excess glucose to fatty acids. Increased FFA flux and increased lipogenesis increases the total hepatic FFA pool. The increased hepatic FFA pool can either be converted to triglycerides for storage or transport out of the liver as very low density lipoprotein, or undergo oxidation in mitochondria, peroxisomes, or endoplasmic reticulum. Increased reactive oxygen species generated during fatty acid oxidation causes lipid peroxidation, which subsequently increases oxidative stress, inflammation, and fibrosis. FIGURE 20.5

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 7 Fatty liver disease along with hepatic fibrosis. (A) Patient with NAFLD shows significant macrovesicular (arrowhead) and microvesicular steatosis (blue arrowhead) in a representative H&E stain. (B) Masson trichrome staining of liver from mouse on methionine and choline-deficient diet for 4 weeks reveals hepatic fibrosis (arrow) along with macrovesicular steatosis (arrowheads). FIGURE 20.6

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 8 Histology and immunohistochemistry for β-catenin in pediatric hepatoblastomas. (A) H&E displaying embryonal pattern of hepatoblastoma. (B) H&E displaying small cell embryonal hepatoblastoma. (C) H&E displaying fetal hepatoblastoma. (D) Nuclear and cytoplasmic localization of β-catenin in an embryonal hepatoblastoma. (E) Nuclear localization of β-catenin along with some membranous staining in a fetal hepatoblastoma. FIGURE 20.7

Companion site for Molecular Pathology Copyright © 2009 by Academic Press. All rights reserved. 9 Histology of hepatic adenoma and HCC in mouse model of chemical carcinogenesis and HCC in patients. (A) A hepatic adenoma (*) is evident on H&E in mice 6 months after diethylnitrosamine (DEN) injection. (B) HCC (*) is evident in mouse liver 9 months after DEN injection. (C) H&E show abnormal trabecular pattern (arrowheads) in HCC patient. (D) H&E showing fibrolamellar variant of HCC in a patient with lamellar fibrosis (arrowhead) pattern surrounding large tumor cells (arrows). FIGURE 20.8