• Can we Promote Liver Regeneration in Patients with Decompensated Cirrhosis?

Can we Promote Liver Regeneration in Patients with Decompensated Cirrhosis?

The combination of granulocyte colony-stimulating factor (G-CSF) and a long-acting form of erythropoietin increases survival of patients with decompensated cirrhosis, researchers report in the June issue of Gastroenterology. The growth factor combination also improved liver function and reduced risk for septic shock within 1 y of treatment.

Decompensation in patients with end-stage liver disease is characterized by the presence of ascites, variceal bleeding, encephalopathy, and/or jaundice. The only established treatment is liver transplantation.

G-CSF is a cytokine that can mobilize hematopoietic stem cells, increase production of hepatocyte growth factor, and induce hepatic progenitor cells to proliferate. It has been shown to increase survival of patients with acute-on-chronic liver failure.

Erythropoietin regulates red blood cell production by promoting erythroid differentiation and initiating hemoglobin synthesis. It was reported to stimulate hepatic regeneration and increase liver function in animals.

Chandan Kumar Kedarisetty et al therefore investigated whether these growth factors could induce liver regeneration and help patients with decompensated cirrhosis.

In a double-blind study, 55 patients were randomly assigned to groups given subcutaneous G-CSF (5 µg/kg/day for 5 days and then every third day, for a total of 12 doses) plus subcutaneous darbepoetin α (a long-acting erythropoietin; 40 µg/week for 4 weeks) or placebo. Both groups received standard medical care and were followed for 12 months.

A significantly higher proportion of patients in the growth factor group survived for the following 12 months (68.6%) than in the placebo group (26.9%, see figure).

Kaplan-Meier curve showing the overall survival at 12 months in the growth factor and control groups.

Kaplan-Meier curve showing the overall survival at 12 months in the growth factor and control groups.

The growth factor group also had significant improvements in liver function, based on Child-Pugh and model for end-stage liver disease scores.

The need for large-volume paracentesis was significantly reduced in growth factor group, compared with controls, and a lower proportion developed septic shock (6.9%) during the follow-up period, compared with controls (38.5%). No major adverse events were observed in either group. There was no significant difference in hepatic venous pressure gradient between groups.

The authors observed that by 1 month after treatment, the mean level of α-fetoprotein was significantly higher in the growth factor group (6.6±3.6 ng/mL) than in controls (4.7±2.7 ng/mL), indicating increased hepatic regeneration.

Patients in the growth factor group who underwent repeat liver biopsy were found to have an increased density of CD34+, CD133+ proliferating cells at 1 month, compared with controls. The authors state that this is a sign of hepatic regeneration.

Kedarisetty et al explain that the 2 growth factors act on different cell lineages in the bone marrow.

How do these factors promote liver regeneration? The authors explain that bone marrow and liver share a developmental relationship, since hematopoiesis occurs in the fetal liver. The bone marrow is a reservoir for multiple stem cell populations. Systemic administration of G-CSF has been shown to mobilize hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells to move into the peripheral circulation after injury.

Similarly, erythropoietin can activate endothelial progenitor cells and increase their regenerative roles via the PI3KAKT signaling pathway.

Kedarisetty et al state that this is the first double-blind randomized controlled study to show clinical benefit and an overall increased survival from combination of G-CSF and erythropoietin in patients with decompensated liver disease. They add that it is also the first human study to test the effects of erythropoietin in patients with decompensated liver cirrhosis and demonstrate its potential in hepatic regeneration.

However, the findings require confirmation in larger cohort of patients with decompensated liver disease.

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