Work

Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity

Year: 2014

Type: article

Abstract: UNLABELLED: Hedgehog (Hh) ligand production by ballooned hepatocytes drives nonalcoholic steatohepatitis (NASH) progression in mice. The NIDDK-sponsored PIVENS trial (NCT00063622) showed that vitamin E (VitE) improved NASH. We investigated whether VitE treatment and improvement in NASH were associated with changes in Hh pathway activity. Immunohistochemistry (IHC) was performed on both pre- and posttreatment liver biopsies of 59 PIVENS patients randomized to VitE (n = 30) or placebo (n = 29). Sonic Hh (Shh) ligand-producing cells and Shh-responsive cells were quantified. The latter was accomplished by triple IHC for gli2+ (marker of Hh signaling), sox-9 (progenitor marker), and α-smooth muscle actin (α-SMA; myofibroblast marker). Ballooned hepatocytes were quantified by keratin 8/18 and ubiquitin (K8/18/Ub) staining. IHC results were correlated with primary clinical and histologic PIVENS data. Pretreatment clinical, histologic, and IHC parameters did not differ significantly in the two treatment groups. Regardless of treatment arm, the number of Shh+ hepatocytes correlated with K8/18/Ub foci (r(2) = 0.47, P < 0.001) and aspartate aminotransferase (AST) (r(2) = 0.15, P = 0.002). Treatment-related changes in the numbers of Shh+ hepatocytes correlated with changes in serum AST (partial r(2) = 0.75, P < 0.0001), hepatocyte ballooning (P = 0.004), the ductular reaction (i.e., numbers of gli2+/sox9+ cells; P = 0.03 and α-SMA+ cells; P = 0.10), and fibrosis stage (P = 0.02). Treatment response was associated with a greater decrease in Shh+ hepatocytes than nonresponse (P = 0.007). The VitE group demonstrated a greater reduction in K8/18/Ub+ foci (P < 0.08) and Shh+ hepatocytes (P < 0.05) than the placebo group, effects that became more significant after correction for baseline differences and multiple linear regression analysis. CONCLUSION: During PIVENS, treatment response correlated with loss of Shh+ hepatocytes and improvement in Hh-regulated processes that promote NASH progression.

Source: Hepatology

DOI: 10.1002/hep.27235

Authors: Cynthia D. Guy, Ayako Suzuki, Manal F. Abdelmalek, James L. Burchette, Anna Mae Diehl, for the NASH CRN

Institutions: Duke Medical Center, Duke University

Language: English

Topic: Liver Disease Diagnosis and Treatment

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute of Diabetes and Digestive and Kidney Diseases