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.2012 Jun;55(6):1711-21.
doi: 10.1002/hep.25559. Epub 2012 Apr 18.

Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease

Collaborators, Affiliations

Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease

Cynthia D Guy et al. Hepatology.2012 Jun.

Abstract

The Hedgehog (HH)-signaling pathway mediates several processes that are deregulated in patients with metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome generally correlate. Therefore, we hypothesized that the level of HH-pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and HH-pathway activation, immunohistochemistry was performed on liver biopsies from a large, well-characterized cohort of NAFLD patients (n = 90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased HH activity (evidenced by accumulation of HH-ligand-producing cells and HH-responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each P < 0.0001), supporting a relationship between HH-pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both P < 0.03). In addition, various clinical parameters that have been linked to histologically advanced NAFLD, including increased patient age (P < 0.005), body mass index (P < 0.002), waist circumference (P < 0.0007), homeostatic model assessment of insulin resistance (P < 0.0001), and hypertension (P < 0.02), correlated with hepatic HH activity.

Conclusion: In NAFLD patients, the level of hepatic HH-pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the HH-signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with metabolic syndrome.

Copyright © 2012 American Association for the Study of Liver Diseases.

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Figures

Figure 1
Figure 1. Shh expression correlates with fibrosis stage in NAFLD
Photomicrographs of Shh immunohistochemistry in patients with S0(a), S2(b), S3(c) and S4(d) fibrosis show increased numbers of positive cells with increased fibrosis stage (x400 magnification). The immunohistochemistry scoring results were semi-quantified into 5 ranks and the results were plotted according to the fibrosis stage as scored by the NASH CRN Pathology Committee using trichrome-stained liver sections(e). Closed circles represent individual subjects. The bold line represents the mean value, while whiskers with horizontal lines (upper and lower) represent the standard error. p < 0.0001 (Kruskal-Wallis test). p<0.005 (α-level adjusted for 10 post-hoc comparison pairs): * (vs. stage 1 and 2) and ** (vs. stage 0, 1, and 2).
Figure 1
Figure 1. Shh expression correlates with fibrosis stage in NAFLD
Photomicrographs of Shh immunohistochemistry in patients with S0(a), S2(b), S3(c) and S4(d) fibrosis show increased numbers of positive cells with increased fibrosis stage (x400 magnification). The immunohistochemistry scoring results were semi-quantified into 5 ranks and the results were plotted according to the fibrosis stage as scored by the NASH CRN Pathology Committee using trichrome-stained liver sections(e). Closed circles represent individual subjects. The bold line represents the mean value, while whiskers with horizontal lines (upper and lower) represent the standard error. p < 0.0001 (Kruskal-Wallis test). p<0.005 (α-level adjusted for 10 post-hoc comparison pairs): * (vs. stage 1 and 2) and ** (vs. stage 0, 1, and 2).
Figure 2
Figure 2. Shh expression correlates with hepatocyte ballooning
Photomicrographs of Shh immunohistochemistry in patients with Grade 0(a), Grade 1(b), and Grade 2(c) ballooning show increased numbers of positive cells with increased ballooning grade (x400 magnification). Shh expression was plotted relative to the grade of hepatocyte ballooning as scored by the NASH CRN Pathology Committee using H&E-stained liver sections(d). Closed circles represent individual subjects. The bold line represents the mean value, while whiskers with horizontal lines (upper and lower) represent the standard error. p < 0.0001 (Kruskal-Wallis test); * p<0.017 vs. grade 1 and 2 (α-level adjusted for 3 post-hoc comparison pairs).
Figure 2
Figure 2. Shh expression correlates with hepatocyte ballooning
Photomicrographs of Shh immunohistochemistry in patients with Grade 0(a), Grade 1(b), and Grade 2(c) ballooning show increased numbers of positive cells with increased ballooning grade (x400 magnification). Shh expression was plotted relative to the grade of hepatocyte ballooning as scored by the NASH CRN Pathology Committee using H&E-stained liver sections(d). Closed circles represent individual subjects. The bold line represents the mean value, while whiskers with horizontal lines (upper and lower) represent the standard error. p < 0.0001 (Kruskal-Wallis test); * p<0.017 vs. grade 1 and 2 (α-level adjusted for 3 post-hoc comparison pairs).
Figure 3
Figure 3. Numbers of Gli2+ cells correlate with fibrosis stage and grade of portal inflammation
Photomicrographs of Gli2 immunohistochemistry in patients with S0(a), S2(b), S3(c), and S4(d) fibrosis show increased numbers of positive cells (nuclear staining) with increased fibrosis stage (x400 magnification). The Gli2 staining scores were plotted relative to fibrosis stage(e), as well as portal inflammation grade(f). Closed circles represent individual subjects. The bold line represents the mean value, while whiskers with horizontal lines (upper and lower) represent the standard error. Significant stage/grade-related differences are shown, *p < 0.005 (vs. stage 0, 1 ,and 2)(e) and *p<0.017 vs. grade 2 (α-level adjusted for 10 and 3 post-hoc comparison pairs for fibrosis stage and portal inflammation grade, respectively).
Figure 3
Figure 3. Numbers of Gli2+ cells correlate with fibrosis stage and grade of portal inflammation
Photomicrographs of Gli2 immunohistochemistry in patients with S0(a), S2(b), S3(c), and S4(d) fibrosis show increased numbers of positive cells (nuclear staining) with increased fibrosis stage (x400 magnification). The Gli2 staining scores were plotted relative to fibrosis stage(e), as well as portal inflammation grade(f). Closed circles represent individual subjects. The bold line represents the mean value, while whiskers with horizontal lines (upper and lower) represent the standard error. Significant stage/grade-related differences are shown, *p < 0.005 (vs. stage 0, 1 ,and 2)(e) and *p<0.017 vs. grade 2 (α-level adjusted for 10 and 3 post-hoc comparison pairs for fibrosis stage and portal inflammation grade, respectively).
Figure 3
Figure 3. Numbers of Gli2+ cells correlate with fibrosis stage and grade of portal inflammation
Photomicrographs of Gli2 immunohistochemistry in patients with S0(a), S2(b), S3(c), and S4(d) fibrosis show increased numbers of positive cells (nuclear staining) with increased fibrosis stage (x400 magnification). The Gli2 staining scores were plotted relative to fibrosis stage(e), as well as portal inflammation grade(f). Closed circles represent individual subjects. The bold line represents the mean value, while whiskers with horizontal lines (upper and lower) represent the standard error. Significant stage/grade-related differences are shown, *p < 0.005 (vs. stage 0, 1 ,and 2)(e) and *p<0.017 vs. grade 2 (α-level adjusted for 10 and 3 post-hoc comparison pairs for fibrosis stage and portal inflammation grade, respectively).
Figure 4
Figure 4. Hepatic accumulation of liver progenitor cells increases with fibrosis stage, portal inflammation, and hepatocyte ballooning in NAFLD
Photomicrographs of liver sections double-stained for keratin 7 (blue) and Gli2 (brown) in patients with S0(a), S2(b), S3(c) and S4(d) fibrosis show increased numbers of positive cells with increased fibrosis stage (x400 magnification). Keratin 7-positive cells and Gli2-positive cells were counted in double-stained liver biopsy sections. The average cell counts (per x400 HPF) were plotted in relationship to fibrosis(e), portal inflammation(f), and hepatocyte ballooning(g). In each graph, closed circles represent individual subjects. The bold line represents the mean value while whiskers with horizontal lines (upper and lower) represent standard error. p< 0.05, 0.03, and 0.004 for fibrosis, portal inflammation, and ballooning, respectively (Kruskal-Wallis test).
Figure 4
Figure 4. Hepatic accumulation of liver progenitor cells increases with fibrosis stage, portal inflammation, and hepatocyte ballooning in NAFLD
Photomicrographs of liver sections double-stained for keratin 7 (blue) and Gli2 (brown) in patients with S0(a), S2(b), S3(c) and S4(d) fibrosis show increased numbers of positive cells with increased fibrosis stage (x400 magnification). Keratin 7-positive cells and Gli2-positive cells were counted in double-stained liver biopsy sections. The average cell counts (per x400 HPF) were plotted in relationship to fibrosis(e), portal inflammation(f), and hepatocyte ballooning(g). In each graph, closed circles represent individual subjects. The bold line represents the mean value while whiskers with horizontal lines (upper and lower) represent standard error. p< 0.05, 0.03, and 0.004 for fibrosis, portal inflammation, and ballooning, respectively (Kruskal-Wallis test).
Figure 4
Figure 4. Hepatic accumulation of liver progenitor cells increases with fibrosis stage, portal inflammation, and hepatocyte ballooning in NAFLD
Photomicrographs of liver sections double-stained for keratin 7 (blue) and Gli2 (brown) in patients with S0(a), S2(b), S3(c) and S4(d) fibrosis show increased numbers of positive cells with increased fibrosis stage (x400 magnification). Keratin 7-positive cells and Gli2-positive cells were counted in double-stained liver biopsy sections. The average cell counts (per x400 HPF) were plotted in relationship to fibrosis(e), portal inflammation(f), and hepatocyte ballooning(g). In each graph, closed circles represent individual subjects. The bold line represents the mean value while whiskers with horizontal lines (upper and lower) represent standard error. p< 0.05, 0.03, and 0.004 for fibrosis, portal inflammation, and ballooning, respectively (Kruskal-Wallis test).
Figure 4
Figure 4. Hepatic accumulation of liver progenitor cells increases with fibrosis stage, portal inflammation, and hepatocyte ballooning in NAFLD
Photomicrographs of liver sections double-stained for keratin 7 (blue) and Gli2 (brown) in patients with S0(a), S2(b), S3(c) and S4(d) fibrosis show increased numbers of positive cells with increased fibrosis stage (x400 magnification). Keratin 7-positive cells and Gli2-positive cells were counted in double-stained liver biopsy sections. The average cell counts (per x400 HPF) were plotted in relationship to fibrosis(e), portal inflammation(f), and hepatocyte ballooning(g). In each graph, closed circles represent individual subjects. The bold line represents the mean value while whiskers with horizontal lines (upper and lower) represent standard error. p< 0.05, 0.03, and 0.004 for fibrosis, portal inflammation, and ballooning, respectively (Kruskal-Wallis test).
Figure 5
Figure 5. Numbers of myofibroblastic cells increase with fibrosis stage
Liver biopsies were stained with α-SMA or vimentin to identify myofibroblastic mesenchymal cells. The liver content of α-SMA positive cells (LSMA)(a) or vimentin-stained cells(b) were quantified as described in the Methods and correlated with fibrosis stage based on NASH CRN Pathology Committee review of trichrome-stained sections. Closed circles represent individual subjects. The bold line represents the mean value while whiskers with horizontal lines (upper and lower) represent standard error. LSMA grade and vimentin grade were higher in livers with advanced fibrosis, p < 0.004 and p<0.002, respectively.(c) The photomicrograph illustrates accumulation of Hh-responsive mesenchymal cells in fibrotic NAFLD. Arrows demonstrate stromal-vascular cells in fibrotic septa double-stained for vimentin (blue) and Gli2 (brown).
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