The Evolution of Severe Steatosis After Bariatric Surgery Is Related to Insulin Resistance
2006; Elsevier BV; Volume: 130; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2006.02.024
ISSN1528-0012
AutoresPhilippe Mathurin, Florent Gonzalez, Olivier Kerdraon, Emmanuelle Leteurtre, Laurent Arnalsteen, Antoine Hollebecque, Alexandre Louvet, Sébastien Dharancy, Perrine Cocq, T. Jany, J. Boitard, Pierre Deltenre, Monique Romon, François Pattou,
Tópico(s)Diet and metabolism studies
ResumoBackground & Aims: In severely obese patients, factors implicated in the evolution of severe steatosis after bariatric surgery remain unresolved. Our aim was to determine whether insulin resistance (IR) influences the histologic effects induced by bariatric surgery. Methods: We prospectively included 185 severely obese patients (body mass index ≥35 kg/m2) referred for bariatric surgery. The evolution of IR (IR index = 1/quantitative insulin sensitivity check index) and liver injury with consecutive biopsy was concomitantly assessed before and 1 year after surgery. Results: At preoperative biopsy, 27% of severely obese patients disclosed severe steatosis (≥60%). The alanine aminotransferase (P = .01) and IR indexes (P = .04) were independent predictive factors of severe steatosis at baseline. One year after surgery, surgical treatment induced a decrease in body mass index (9.5 kg/m2; P < .0001), steatosis score (8.5%; P < .0001), and IR index (0.29; P < .0001). The preoperative IR index (P = .01) and preoperative steatosis (P = .006) were independent predictive factors in the persistence of severe steatosis after surgery. Moderate or severe steatosis was more frequently observed in patients who had conserved a higher IR index after surgery than in patients who had improved their IR index (44% vs 20.2%; P = .04). Conclusions:: IR was independently associated with severe steatosis and predicted its persistence after surgery. The amelioration of IR after surgery is associated with a decrease in the amount of fat. Taken together, the results of this prospective study in severely obese patients demonstrate that severe steatosis and its evolution after surgery are intimately connected with IR. Background & Aims: In severely obese patients, factors implicated in the evolution of severe steatosis after bariatric surgery remain unresolved. Our aim was to determine whether insulin resistance (IR) influences the histologic effects induced by bariatric surgery. Methods: We prospectively included 185 severely obese patients (body mass index ≥35 kg/m2) referred for bariatric surgery. The evolution of IR (IR index = 1/quantitative insulin sensitivity check index) and liver injury with consecutive biopsy was concomitantly assessed before and 1 year after surgery. Results: At preoperative biopsy, 27% of severely obese patients disclosed severe steatosis (≥60%). The alanine aminotransferase (P = .01) and IR indexes (P = .04) were independent predictive factors of severe steatosis at baseline. One year after surgery, surgical treatment induced a decrease in body mass index (9.5 kg/m2; P < .0001), steatosis score (8.5%; P < .0001), and IR index (0.29; P < .0001). The preoperative IR index (P = .01) and preoperative steatosis (P = .006) were independent predictive factors in the persistence of severe steatosis after surgery. Moderate or severe steatosis was more frequently observed in patients who had conserved a higher IR index after surgery than in patients who had improved their IR index (44% vs 20.2%; P = .04). Conclusions:: IR was independently associated with severe steatosis and predicted its persistence after surgery. The amelioration of IR after surgery is associated with a decrease in the amount of fat. Taken together, the results of this prospective study in severely obese patients demonstrate that severe steatosis and its evolution after surgery are intimately connected with IR. Obesity is associated with severe complications such as arterial hypertension, diabetes, coronary heart disease, stroke, sleep apnea, and peripheral vascular disease.1Keller K.B. Lemberg L. 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Nonalcoholic fatty liver disease improvement in liver histological analysis with weight loss.Hepatology. 2004; 39: 1647-1654Crossref PubMed Scopus (653) Google Scholar That study had the classic bias of selection, because consecutive biopsies were performed in only 36 of the 197 patients treated by bariatric surgery. Therefore, studies with a prospective design of a histologic survey are needed. We focused on the role of IR in obesity-induced liver injury after bariatric surgery to gain additional insight into the pathogenesis of NAFLD. Thus, this is the first prospective study on a large cohort of unselected severely obese patients that concurrently evaluated both the evolution of liver injury using sequential biopsies and IR before and 1 year after surgery. Between 1994 and 2003, 185 severely to morbidly obese patients were referred to our unit for surgical treatment of obesity. To be eligible for the study, all patients had to have fulfilled the following criteria: (1) severe obesity (BMI ≥35 kg/m2) with comorbidity/comorbidities or morbid obesity alone (BMI ≥40 kg/m2) for at least 5 years and resistance to medical treatment; (2) the absence of medical or psychological contraindications for bariatric surgery; (3) the absence of current excessive drinking, as defined by an average daily consumption of alcohol of <20 g/day for women and 1.2 g/L, cholesterol level >2.4 g/L, and serum triglyceride level >1.5 g/L, respectively. In the present study, we assessed IR using the quantitative insulin sensitivity check index (QUICKI). This method is significantly correlated with the hyperinsulinemic euglycemic glucose clamp and is considered a valid method for evaluating IR in obese patients.41Katz A. Nambi S.S. Mather K. Baron A.D. Follmann D.A. Sullivan G. Quon M.J. 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Liver biopsy.N Engl J Med. 2001; 344: 495-500Crossref PubMed Scopus (1861) Google Scholar Steatosis was quantified in the percentage of hepatocytes containing fat droplets (steatosis amount) and graded using the following scale: 0, absent (<5% of hepatocytes affected); 1, mild ( 60% of hepatocytes affected).43Brunt E.M. Janney C.G. Di Bisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3152) Google Scholar, 44Silverman J.F. O’Brien K.F. Long S. Leggett N. Khazanie P.G. Pories W.J. Norris H.T. Caro J.F. Liver pathology in morbidly obese patients with and without diabetes.Am J Gastroenterol. 1990; 85: 1349-1355PubMed Google Scholar NASH was defined as the presence of steatosis plus mixed lobular inflammation plus hepatocellular ballooning2Neuschwander-Tetri B.A. Caldwell S.H. Nonalcoholic steatohepatitis summary of an AASLD single topic conference.Hepatology. 2003; 37: 1202-1219Crossref PubMed Scopus (1796) Google Scholar and was graded according to Brunt’s score as follows: 0, absent; 1, mild; 2, moderate; and 3, severe.43Brunt E.M. Janney C.G. Di Bisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3152) Google Scholar Liver fibrosis was assessed semiquantitatively using a 5-grade scale: F0, normal; F1, focal pericellular fibrosis in zone 3; F2, perivenular and pericellular fibrosis confined to zones 2 and 3 with or without portal/periportal fibrosis; F3, bridging or extensive fibrosis with architectural distortion and no obvious cirrhosis; and F4, cirrhosis.43Brunt E.M. Janney C.G. Di Bisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3152) Google Scholar Histologic analysis classified the liver as normal when the amount of steatosis was 60%. The relationship between severe steatosis and various risk factors was studied using a univariate comparison followed by multivariate analysis using logistic regression. In univariate analysis, 2 groups were compared according to the presence or absence of severe steatosis. Baseline variables that reached a univariate P value ≤.05 were included in multivariate analysis. In multivariate analysis, severe steatosis was the dependent variable. Regression coefficients were expressed with their standard error. Statistical analysis was performed using NCSS 2001 software (NCSS, Kaysville, UT). A total of 185 consecutive obese patients (148 women and 37 men; mean age, 41 ± 9 years) with a mean BMI at 49 ± 8 kg/m2 were prospectively included. They were referred for undergoing bariatric surgery for morbid obesity in 176 cases (95%) or severe obesity with comorbidity (arterial hypertension and/or diabetes mellitus) in 9 cases (5%). Biliointestinal bypass and gastric band procedures were performed in 71 patients (42%) and 100 patients (58%), respectively. Bariatric surgery was contraindicated for suspicion of cirrhosis in 14 patients with the following patterns: (1) biologic abnormalities (low platelet count, low prothrombin time, or abnormal bilirubin levels) suggestive of cirrhosis and observed at inclusion in 8 patients and (2) macroscopic appearance of cirrhosis preoperatively diagnosed in 6 cases, leading to postponement of bariatric surgery. Among these 14 patients, cirrhosis was biopsy proven in 10 cases. The main clinical, biologic, and histologic characteristics of the patients are given in Table 1. ALT levels were normal in 53 patients (28%), with a common threshold of 45 IU/L used as the upper normal range. Liver biopsy was performed during the surgical procedure. Histologic analysis was not available in 21 patients; the size of the liver biopsy specimen was insufficient to permit histologic analysis in 17 cases and biopsy was postponed because of macroscopic diagnosis of cirrhosis by the surgeon in 4 cases.Table 1Clinical, Biologic, and Histologic Characteristics of the 185 Patients Before Bariatric SurgeryFemale sex, no. (%)148 (80)Age (y), median (95% CI)40.6 (39–42.8)BMI (kg/m2), median (95% CI)47.1 (46.1–48.2)Diabetes mellitus, no. (%)31 (16.8)aTwelve percent of patients below the median IR index were diabetic as compared with 35.4% of patients above this cutoff (P = .002). Seventy-four percent of diabetic patients had an IR index above the median. None of the diabetic patients were treated with insulin.Arterial hypertension, no. (%)69 (37.3)Cholesterol level (g/L), median (95% CI)2.06 (1.97–2.14)Hypercholesterolemia, no. (%)71 (44.7)Serum triglyceride level (g/L), median (95% CI)1.34 (1.25–1.43)Hypertriglyceridemia, no. (%)84 (53.9)Hypothyroidism, no. (%)18 (9.7)ALT level (IU/L), median (95% CI)21 (19–25)GGT level (IU/L), median (95% CI)29 (26–36)Fasting blood glucose level (g/L), median (95% CI)1 (0.97–1.04)Fasting serum insulin level (IU/L), median (95% CI)12.9 (11.3–14.7)IR index (1/QUICKI), median (95% CI)3.13 (3.07–3.19)Amount of steatosis (%), median (95% CI)bLiver histology was classified as normal (for more details, see Methods) in 50 patients (30%).20 (15–30)Severe steatosis, no. (%)44 (26.8)NASH, no. (%)24 (14.4)Fibrosis F0/F1/F2/F3/F4, no. (%)136 (81)/17 (10)/4 (2)/1 (1)/10 (6)cTen patients had cirrhosis and were contraindicated for surgery.a Twelve percent of patients below the median IR index were diabetic as compared with 35.4% of patients above this cutoff (P = .002). Seventy-four percent of diabetic patients had an IR index above the median. None of the diabetic patients were treated with insulin.b Liver histology was classified as normal (for more details, see Methods) in 50 patients (30%).c Ten patients had cirrhosis and were contraindicated for surgery. Open table in a new tab BMI was similar in patients with NASH and patients without NASH (47.4 kg/m2 [95% CI, 41.3–51.1] vs 47.3 kg/m2 [95% CI, 46.2–48.5]; not significant). Conversely, the insulin resistance index was significantly higher in patients with NASH than in those without NASH (3.4 [95% CI, 3.08–3.71] vs 3.1 [95% CI, 3.06–3.17]; P = .004). Patients treated by biliointestinal bypass and those treated by gastric banding were similar in terms of clinical and biologic characteristics (Table 2). Although there was no difference between the 2 groups in terms of steatosis and fibrosis, a higher frequency of NASH was observed in the gastric band group (15% vs 3%; P = .03).Table 2Comparison of Bypass and Gastric Band Groups Before SurgeryVariablesBiliointestinal bypass group(n = 71)Gastric band group(n = 100)Significant P valueFemale sex, no. (%)58 (81.7)85 (85)NSAge (y), median (95% CI)40.5 (37.6–45.2)39.3 (36.7–41.6)NSBMI (kg/m2), median (95% CI)48.5 (46.3–52.2)46.6 (45.2–47.8)NSDiabetes mellitus, no. (%)10 (14)15 (15)NSArterial hypertension, no. (%)29 (41)34 (34)NSHypercholesterolemia, no. (%)22 (42)43 (43)NSHypertriglyceridemia, no. (%)24 (46)54 (57)NSHypothyroidism, no. (%)4 (6)13 (13)NSALT level (IU/L), median (95% CI)19 (17–26)20 (18–23)NSGGT level (IU/L), median (95% CI)28 (23–36)27 (23–35)NSIR index, median (95% CI)3.08 (3.01–3.13)3.15 (3.08–3.25)NSAmount of steatosis (%), median (95% CI)25 (15–50)20 (15–30)NSSevere steatosis, no. (%)19 (29)22 (24)NSNASH, no. (%)2 (3)12 (13).03Fibrosis F0/F1/F2/F3/F4, no. (%)57 (88)/8 (12)/0/0/078 (87)/8 (9)/3 (3)/1 (1)/0NSNormal liver, no. (%)17 (26)33 (37)NSNS, not significant. Open table in a new tab NS, not significant. One year after bariatric surgery, the median weight loss was 27 kg (95% CI, 23–29), corresponding to a median decrease in BMI of 9.5 kg/m2, and all important biologic parameters of the metabolic syndrome were improved (Table 3). In addition, bariatric surgery induced a marked improvement in liver injury. ALT and GGT levels decreased significantly, and the amount of steatosis was significantly reduced with a median decrease of 8.5% (Table 3). The percentage of patients disclosing features of NASH decreased (10% vs 6.8%; P = .37), although not significantly, and NASH disappeared in 75% of patients showing histologic features of NASH before surgery. Although the fibrosis score increased significantly 1 year after surgery, the mean magnitude of the increase (0.24) and the mean score of fibrosis on the second biopsy (0.38) were not clinically relevant.Table 3One-Year Effects of Bariatric Surgery on Clinical, Biologic, and Histologic ParametersVariablesBefore surgery1 year after surgeryDifferenceSignificant P valueBMI (kg/m2), median (95% CI)47.1 (46–48.4)38.1 (36.6–39.9)9.5 (8.3–10.4)<.0001Arterial hypertension, no. (%)70 (37.6)46 (30.3)7.3%NSCholesterol level (g/L), median (95% CI)2.1 (1.99–2.16)1.8 (1.65–1.93)0.21 (0.15–0.27)<.0001Serum triglyceride level (g/L), median (95% CI)1.35 (1.25–1.46)1.1 (0.98–1.2)03 (0.18–0.39)<.0001IR index, median (95% CI)3.
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