Table 1.

The hedgehog pathway in liver disease.

Liver Regeneration	Chronic liver disease	Liver Cancer
Animal models of partial hepatectomy present transient activation of the Hh pathway. Inhibition of the Hh pathway results in decreased recovery of the liver mass and increased mortality. Additionally, administration of Ihh accelerates liver regeneration and improves outcome. Humans submitted to ALPPS show increase in Ihh, which associates with accelerated recovery of liver mass as compared to the classical two-stage hepatectomy.	Activation of the Hh pathway in animal models and humans with different types of chronic liver disease (NAFLD, ALD, chronic viral hepatitis, cholangiopathies, radiation liver injury and schistosomiasis). Pharmacological or genetic inhibition of the Hh pathway decreases liver injury and fibrosis in animal models. Patients with genetic inhibition of the Hh pathway have more frequently NAFLD, but with a less fibrogenic phenotype.	Activation of the Hh pathway in different human liver cancers: HCC, cholangiocarcinoma and infantile hepatoplastoma. In patients with HCC, Hh activation associates with increased tumor burden, invasion, metastatic disease, chemoresistance and worse prognosis. Smo inhibition is effective in animal models of HCC. Phase I studies on Smo inhibition in HCC ongoing.

Hh, hedgehog; Ihh, Indian hedgehog; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; NAFLD, nonalcoholic fatty liver disease; ALD, alcoholic liver disease; HCC, hepatocellular carcinoma.