Alcoholic Hepatitis Survival No Better With N-acetylcysteine

Adding N-acetylcysteine to prednisolone therapy failed to significantly improve 6-month survival in patients who had severe acute alcoholic hepatitis, according to a report in the Nov. 10 New England Journal of Medicine.

The combination therapy did improve 1-month survival compared with standard prednisolone treatment alone, but that benefit did not persist, said Dr. Eric Nguyen-Khac of Amiens (France) University Hospital, and his associates.

Severe acute alcoholic hepatitis is accompanied by mitochondrial depletion of glutathione, a major cellular antioxidant. Researchers have proposed that adding an antioxidant such as N-acetylcysteine to standard glucocorticoid therapy for this condition "would have the advantage of both acting on the inflammatory process and reconstituting cellular glutathione reserves," Dr. Nguyen-Khac and his colleagues said (N. Engl. J. Med. 2011;365:1,781-9).

In addition, N-acetylcysteine has been shown to protect the liver in chronic alcoholic hepatitis and in mouse models of acute alcoholic hepatitis.

The investigators tested this theory in a trial involving 180 patients treated over a 5-year period at 11 university hospitals in France. Study subjects were randomly assigned to receive oral prednisolone plus 5 days of intravenous N-acetylcysteine (89 patients) or oral prednisolone plus 5 days of intravenous glucose solution (91 patients serving as controls) and were followed at intervals for 6 months.

All study subjects were allowed concomitant therapy with diuretics, albumin, and sodium restriction for ascites and with beta-blockers for portal hypertension, as needed. A total of 57 subjects died during the study.

The final analysis included 174 study subjects. The primary end point, mortality at 6 months, occurred among 23 of 85 patients (27%) in the combined-therapy group and 34 of 89 patients (38%) in the control group, a difference that was not significant.

A secondary end point, mortality at 1 month, was significantly better with combined therapy (7 of 85 patients, or 8%) than with prednisolone alone (21 of 89 patients, or 24%).

The researchers noted that the study may have lacked sufficient power to detect a significant difference at 6 months. "It is also possible that 5 days of N-acetylcysteine was not enough. A longer period of intravenous N-acetylcysteine combined with prednisolone could perhaps be considered, with subsequent oral administration of N-acetylcysteine until 1 month," they said.

Regarding adverse events at 6 months, the rate of hepatorenal syndrome was 12% with combined therapy and 25% in the control group; that of infection was 19% with combined therapy and 42% in the control group. Other complications did not differ between the two groups.

This study was supported by Programme Hospitalier de Recherche Clinique. No conflicts of interest were reported.

Adding N-acetylcysteine to prednisolone therapy failed to significantly improve 6-month survival in patients who had severe acute alcoholic hepatitis, according to a report in the Nov. 10 New England Journal of Medicine.

The combination therapy did improve 1-month survival compared with standard prednisolone treatment alone, but that benefit did not persist, said Dr. Eric Nguyen-Khac of Amiens (France) University Hospital, and his associates.

Severe acute alcoholic hepatitis is accompanied by mitochondrial depletion of glutathione, a major cellular antioxidant. Researchers have proposed that adding an antioxidant such as N-acetylcysteine to standard glucocorticoid therapy for this condition "would have the advantage of both acting on the inflammatory process and reconstituting cellular glutathione reserves," Dr. Nguyen-Khac and his colleagues said (N. Engl. J. Med. 2011;365:1,781-9).

In addition, N-acetylcysteine has been shown to protect the liver in chronic alcoholic hepatitis and in mouse models of acute alcoholic hepatitis.

The investigators tested this theory in a trial involving 180 patients treated over a 5-year period at 11 university hospitals in France. Study subjects were randomly assigned to receive oral prednisolone plus 5 days of intravenous N-acetylcysteine (89 patients) or oral prednisolone plus 5 days of intravenous glucose solution (91 patients serving as controls) and were followed at intervals for 6 months.

All study subjects were allowed concomitant therapy with diuretics, albumin, and sodium restriction for ascites and with beta-blockers for portal hypertension, as needed. A total of 57 subjects died during the study.

The final analysis included 174 study subjects. The primary end point, mortality at 6 months, occurred among 23 of 85 patients (27%) in the combined-therapy group and 34 of 89 patients (38%) in the control group, a difference that was not significant.

A secondary end point, mortality at 1 month, was significantly better with combined therapy (7 of 85 patients, or 8%) than with prednisolone alone (21 of 89 patients, or 24%).

The researchers noted that the study may have lacked sufficient power to detect a significant difference at 6 months. "It is also possible that 5 days of N-acetylcysteine was not enough. A longer period of intravenous N-acetylcysteine combined with prednisolone could perhaps be considered, with subsequent oral administration of N-acetylcysteine until 1 month," they said.

Regarding adverse events at 6 months, the rate of hepatorenal syndrome was 12% with combined therapy and 25% in the control group; that of infection was 19% with combined therapy and 42% in the control group. Other complications did not differ between the two groups.

This study was supported by Programme Hospitalier de Recherche Clinique. No conflicts of interest were reported.

Adding N-acetylcysteine to prednisolone therapy failed to significantly improve 6-month survival in patients who had severe acute alcoholic hepatitis, according to a report in the Nov. 10 New England Journal of Medicine.

The combination therapy did improve 1-month survival compared with standard prednisolone treatment alone, but that benefit did not persist, said Dr. Eric Nguyen-Khac of Amiens (France) University Hospital, and his associates.

Severe acute alcoholic hepatitis is accompanied by mitochondrial depletion of glutathione, a major cellular antioxidant. Researchers have proposed that adding an antioxidant such as N-acetylcysteine to standard glucocorticoid therapy for this condition "would have the advantage of both acting on the inflammatory process and reconstituting cellular glutathione reserves," Dr. Nguyen-Khac and his colleagues said (N. Engl. J. Med. 2011;365:1,781-9).

In addition, N-acetylcysteine has been shown to protect the liver in chronic alcoholic hepatitis and in mouse models of acute alcoholic hepatitis.

The investigators tested this theory in a trial involving 180 patients treated over a 5-year period at 11 university hospitals in France. Study subjects were randomly assigned to receive oral prednisolone plus 5 days of intravenous N-acetylcysteine (89 patients) or oral prednisolone plus 5 days of intravenous glucose solution (91 patients serving as controls) and were followed at intervals for 6 months.

All study subjects were allowed concomitant therapy with diuretics, albumin, and sodium restriction for ascites and with beta-blockers for portal hypertension, as needed. A total of 57 subjects died during the study.

The final analysis included 174 study subjects. The primary end point, mortality at 6 months, occurred among 23 of 85 patients (27%) in the combined-therapy group and 34 of 89 patients (38%) in the control group, a difference that was not significant.

A secondary end point, mortality at 1 month, was significantly better with combined therapy (7 of 85 patients, or 8%) than with prednisolone alone (21 of 89 patients, or 24%).

The researchers noted that the study may have lacked sufficient power to detect a significant difference at 6 months. "It is also possible that 5 days of N-acetylcysteine was not enough. A longer period of intravenous N-acetylcysteine combined with prednisolone could perhaps be considered, with subsequent oral administration of N-acetylcysteine until 1 month," they said.

Regarding adverse events at 6 months, the rate of hepatorenal syndrome was 12% with combined therapy and 25% in the control group; that of infection was 19% with combined therapy and 42% in the control group. Other complications did not differ between the two groups.

This study was supported by Programme Hospitalier de Recherche Clinique. No conflicts of interest were reported.