A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis.
OBJECTIVE
Insulin resistance and oxidative stress contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). We conducted a pilot study for the following reasons: (1) to test the hypothesis that a combination of an antioxidant (vitamin E) and an insulin sensitizer (pioglitazone) would be superior to vitamin E alone for the treatment of NASH, and (2) to define the effects of these interventions on insulin-sensitive metabolic functions and correlate the effects with changes in liver histology.


METHODS
A randomized prospective trial was performed to compare the efficacy and safety of vitamin E alone (400 IU/day) vs. vitamin E (400 IU/day) and pioglitazone (30 mg/day) in nondiabetic, noncirrhotic subjects with NASH. Metabolic functions were assessed by a 2-step, hyperinsulinemic (10 and 40 mU/m2/min) euglycemic clamp.


RESULTS
A total of 10 patients were randomized to each arm. Two patients on combination therapy discontinued treatment; one because of pregnancy and the other because of hepatotoxicity. Treatment with vitamin E only produced a significant decrease in steatosis (mean grade, 2.2 vs. 1.4; P < .02). Compared with baseline, combination therapy produced a significant decrease in steatosis (mean, 2.3 vs. 1; P < .002), cytologic ballooning (1.3 vs. 0.2; P < .01), Mallory's hyaline (0.7 vs. 0.2; P < .04), and pericellular fibrosis (1.2 vs. 0.6; P < .03). Although vitamin E had no significant effects, combination therapy produced a significant increase in metabolic clearance of glucose and a decrease in fasting free fatty acid (FFA) and insulin. The decrease in fasting FFA and insulin independently predicted improvement in hepatic steatosis and cytologic ballooning.


CONCLUSIONS
A combination of vitamin E and pioglitazone produces a greater improvement in NASH histology. The improvement in steatosis and cytologic ballooning are related to treatment-associated decreases in fasting FFA and insulin levels.
Sanyal
Arun J
AJ
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Comonwealth University Medical Center, Richmond, VA 23298-0711, USA. ajsanyal@hsc.vcu.edu
Mofrad
Pouneh S
PS
Contos
Melissa J
MJ
Sargeant
Carol
C
Luketic
Velimir A
VA
Sterling
Richard K
RK
Stravitz
R Todd
RT
Shiffman
Mitchell L
ML
Clore
John
J
Mills
Alan S
AS
D020155:3-Hydroxybutyric Acid / Q000032:analysis; D000410:Alanine Transaminase / Q000032:analysis; D000975:Antioxidants / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D000077205:Pioglitazone; D011446:Prospective Studies; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016896:Treatment Outcome; D014810:Vitamin E / Q000627:therapeutic use*
D000975:Antioxidants; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D014810:Vitamin E; D000410:Alanine Transaminase; D005947:Glucose; D020155:3-Hydroxybutyric Acid; D000077205:Pioglitazone