PubMed ID:
22213086
Public Release Type:
Journal
Publication Year: 2012
Affiliation: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
DOI:
https://doi.org/10.1002/hep.25559
Authors:
Hoofnagle JH,
Vuppalanchi R,
Kleiner DE,
Nguyen A,
Chalasani N,
Abdelmalek MF,
Abdelmalek MF,
Abrams SH,
Ackermann S,
Aouizerat B,
Bambha K,
Barlow S,
Bass NM,
Behling C,
Belt P,
Boyett S,
Brancati FL,
Brandt P,
Bringman D,
Brunt EM,
Buie S,
Burchette J,
Byam E,
Clark JM,
Coffey M,
Colvin R,
Contos MJ,
Cummings OW,
DasarathY J,
Dasarathy S,
Dasarathy S,
Derdoy J,
DeVore S,
Diehl AM,
Diehl AM,
Donithan M,
Doo EC,
Durelle J,
Fairly LA,
Ferrell LD,
Filipowski D,
Fishbein MH,
Fuchs M,
Galdzicka S,
Gottfried M,
Grave GD,
Green M,
Gu B,
Guy C,
Guy CD,
Hanna M,
Hassanein T,
Hawkins C,
Hoffmann J,
Hollick R,
Isaacson M,
Jacques K,
Jones A,
Kerkar N,
Killenberg P,
Kim W,
King D,
Klipsch A,
Kohli R,
Kowdley KV,
Kwan S,
Lake K,
Lavine JE,
Liu YC,
Loomba R,
Luketic VA,
Lydecker A,
Mann P,
McCullough AJ,
McCullough AJ,
Merriman R,
Merriman R,
Miriel L,
Mohan P,
Molleston JP,
Mooney J,
Morgan A,
Morris A,
Murray K,
Nair K,
Narayanappa S,
NASH CRN,
Nelson J,
Neuschwander-Tetri BA,
Noble K,
Pabst M,
Pagadala M,
Pan YP,
Patton H,
Pfeifer K,
Piercy D,
Puri P,
Quinn A,
Ragozzino L,
Riazi C,
Robuck PR,
Rogers N,
Rosenthal M,
Rosenthal P,
Rose S,
Sandhu B,
Sanyal AJ,
Sargeant C,
Sargent R,
Saunders C,
Scheimann A,
Schwimmer JB,
Siegner J,
Sirlin C,
Smith M,
Stage M,
Steel T,
Stein T,
Sternberg A,
Stewart S,
Subbarao G,
Suchy F,
Suzuki A,
Thompson J,
Tonascia J,
Torbenson M,
Trinh V,
Unalp A,
Ünalp-Arida A,
Van Natta M,
Vaughn I,
Wang C,
White M,
Whitington PF,
Wilson L,
Xanthakos S,
Yates K,
Yeh M,
Yerian L,
Young M,
Zdanowicz M,
Zein C
Studies:
Nonalcoholic Steatohepatitis Clinical Research Network
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.