Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis

Anne-Sophie Schneck, Rodolphe Anty, Stéphanie Patouraux, Stéphanie Bonnafous, Déborah Rousseau, Cynthia Lebeaupin, Beatrice Bailly-Maitre, Arnaud Sans, Albert Tran, Jean Gugenheim, Antonio Iannelli, Philippe Gual, Anne-Sophie Schneck, Rodolphe Anty, Stéphanie Patouraux, Stéphanie Bonnafous, Déborah Rousseau, Cynthia Lebeaupin, Beatrice Bailly-Maitre, Arnaud Sans, Albert Tran, Jean Gugenheim, Antonio Iannelli, Philippe Gual

Abstract

The long-term effects of bariatric surgery on non-alcoholic steatohepatitis (NASH), focusing on liver injury and hepatocyte apoptosis, are not well-established. We here performed a longitudinal study with paired liver biopsies of nine morbidly obese women (median BMI: 42 [38.7; 45.1] kg/m(2)) with NASH with a median follow-up of 55 [44; 75] months after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. LRYGB surgery was associated with significant weight loss (median BMI loss -13.7 [-16.4; -9.5] kg/m(2)), improved hepatic steatosis in all patients (55.5% with total resolution), and resolution of hepatic inflammation and hepatocyte ballooning in 100 and 88.8% of cases, respectively. Alanine aminotransferase levels dropped to normal values while hepatic activated cleaved caspase-3 levels strongly decreased after a median follow-up of 55 months. Hepatocyte apoptosis, as evaluated by serum caspase-generated keratin-18 fragment, improved within the first year following LRYGB and these improvements persisted for at least 55 months. LRYGB in morbidly obese patients with NASH is thus associated with a long-lasting beneficial impact on hepatic steatohepatitis and hepatocyte death.

Keywords: NAFLD; NASH; bariatric surgery; liver; obesity; steatosis.

Figures

Figure 1
Figure 1
Liver histology analysis of two representative patients (P1 and P2) at baseline and ≥40-months after LRYGB. (A) Liver steatosis was improved (HES staining, x40). (B) Ballooned hepatocytes and hepatic inflammation, both present at baseline, were no longer present on the second liver biopsy (HES staining, x40). (C) P1 had bridging fibrosis (F = 3), P2 had zone three sinusoidal fibrosis and peri-portal sinusoidal fibrosis (F = 2). The second liver biopsy showed a significant improvement in fibrosis (F = 0) in both patients (Sirius red straining, x40). T0, baseline; T ≥ 40, after a ≥40-month follow-up period.
Figure 2
Figure 2
LRYGB in NASH patients improves hepatic steatosis and inflammation in all patients, and improves hepatic fibrosis in the large majority after a median follow-up of 55 months. Nine morbidly obese patients with biopsy-proven NASH underwent LRYGB and had a second liver biopsy at a median follow-up period of 55 [44; 75] months after surgery. From the paired liver biopsies, steatosis (A), inflammatory foci (B), hepatocellular ballooning (C), and fibrosis (E) were evaluated. (D) The NAFLD activity score (NAS) was evaluated as described in Section Materials and Methods. Fibrosis was semi-quantitatively evaluated as follows: 0, none; 1, perisinusoidal or periportal mild (1A); 2, moderate (1B); 3, portal/periportal (1C); 4, perisinusoidal and portal/periportal; 5, bridging fibrosis; 6, cirrhosis. (N) = number of patients.
Figure 3
Figure 3
LRYGB improves liver injury and hepatocyte apoptosis in NASH patients after a median follow-up of 55 months. Serum levels of (A) alanine aminotransferase (ALT) and (B) a marker of hepatocyte apoptosis [caspase-generated keratin 18 fragment (K18 fragment)] and (D) hepatic levels of cleaved caspase 3 were evaluated at baseline and at the median follow-up of 55 [44; 75] months after LRYGB in NASH patients. The levels of K18 fragment were also evaluated (C) at 6 months and at 1 year after a LRYGB and, (E) at baseline (T0) and 1 year (T12) after LRYGB in three additional groups of patients without NAFLD (n = 5), severe steatosis (n = 7), or NASH (n = 7). Results are expressed as the median [25th, 75th percentiles] (A,C,E).

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