The Impact of Bariatric Surgery on Nonalcoholic Steatohepatitis

Charlotte Rabl, M.D.; Guilherme M. Campos, M.D., F.A.C.S.


Semin Liver Dis. 2012;32(1):80-91. 

In This Article

Mechanisms for Improvements in NAFLD and NASH After Bariatric Surgery

The improvements in NAFLD and NASH that occur after bariatric surgery are due to mechanisms related to the significant weight loss and improvements in obesity-associated conditions such as T2DM, insulin resistance, hyperlipidemia, and other components of metabolic syndrome.[80,81] Although the significant and sustained weight loss obtained with bariatric surgery is one of the main factors associated with the remission rate of T2DM and the improvements in liver histology,[13,23,30,81] many other mechanisms that affect carbohydrate and lipid metabolism, some of which are independent of weight loss, have been documented after RYGB and BPD-DS, and in fewer reports after SG as well.[40,82,83] In addition to weight loss, the main mechanisms postulated as being partly responsible for T2DM remission after RYGB and BPD-DS are the altered route of delivery of food content and resultant changes in the release of a variety of gut and pancreatic hormones that affect carbohydrate and lipid metabolism and interfere with hepatic glucose output; differential decrease in quality and distribution of total and regional fat mass; changes in hepatic insulin and free fatty acid metabolism; improvement in associated diseases; and stressors with differential changes in adipocytokines and other cytokines.[42,50,51,76,77,84–87] Though a review of these other mechanisms are beyond the scope of this article, the examples below provide an idea of how, in addition to weight loss, some changes provided by RYGB or BPD-DS may alter glucose and lipid metabolism, and possibly NAFLD and NASH.

The anatomic rearrangement resulting from those procedures alters both fasting levels and postprandial release of gastric, gut, and pancreatic hormones that appear to be related to the improvement in insulin sensitivity.

Glucagon-like Peptide-1

Glucagon-like peptide-1 (GLP-1), which is synthesized in the L cells in the distal portion of the small bowel, increases dramatically and reproducibly in response to feeding in patients who have undergone RYGB, BPD, or BPD-DS.[85,87,88] This is due to the early presentation of the food bolus to the small bowel.[85,88,89] GLP-1 regulates blood glucose by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, possibly decreasing hepatic glucose production and delaying gastric emptying.[90] GLP-1 and related analogues can reduce elevated fasting and postprandial blood glucose levels in diabetic humans, generating intense interest in the use of these agents for the treatment of T2DM.[85] The effects of GLP-1 are mediated by specific binding of GLP-1 to the GLP-1 receptor (GLP-1r).This receptor belongs to the secretin family (type 2) of G-protein coupled receptors, and the downstream signaling is mediated, possibly exclusively, by an increase in intracellular cAMP.[91] Expression of GLP-1r has classically not been mapped in the liver,[92,93] but this has recently been challenged by the observation of reduced liver content of lipids in ob/ob mice[94] after 60 days of treatment with GLP-1. In addition, the presence of functional GLP-1 receptors was demonstrated using Western blots obtained from isolated hepatocytes, and GLP-1 receptor agonist was shown to induce cAMP in primary hepatocytes. Additional evidence comes from Gupta et al,[95] who demonstrated GLP-1r in cultured human hepatocytes, and from Svegliati-Baroni et al,[96] who proved GLP-1r expression in liver biopsies from patients undergoing hepatic resection for focal nodular hyperplasia or hepatic adenoma, and in liver biopsies from patients with NASH. Interestingly, the expression of GLP-1r in the biopsies from patients with NASH was generally lower than the expression in biopsies from the other patient categories. Expression of GLP-1r in liver biopsies from humans shows that GLP-1 regulates expression of transcription factors and enzymes involved in the hepatic metabolism of lipids.[96] All of this evidence challenges the classical view that the liver is not directly influenced by GLP-1.

Peptide YY

Peptide YY (PYY) is synthesized and secreted by the distal small bowel, colon, and rectum. Peripheral administration of PYY3-36, one of the circulating forms of PYY, inhibits food intake. PYY acts on the same hypothalamic neural circuits as leptin, stimulating hypothalamic receptors, decreasing neuropeptide/agouti-related protein and increasing α-melanocyte stimulating hormone levels. In addition to its anorexigenic effect, PYY inhibits gastrointestinal motility as well as pancreatic exocrine and endocrine secretion. Endogenous PYY levels are low in obese patients, suggesting that PYY deficiency may contribute to the pathogenesis. Obese subjects are not resistant to the anorectic effects of PYY.[85,97,98] Gastric bypass appears to be associated with an increase in postprandial levels of PYY.[97–99]


Ghrelin is secreted primarily by oxyntic glands of the stomach fundus.[100] In addition to stimulating growth hormone secretion, ghrelin is a potent appetite stimulant,[101] and ghrelin levels have been shown to correlate with insulin levels and insulin resistance.[102,103] Although ghrelin levels increase during weight loss associated with simple caloric restriction, they seem to decrease markedly after RYGB.[104,105] This decrease in ghrelin may contribute to the success of bypass surgery in inducing both weight loss and improvements in insulin resistance.[104,106–110]

Pancreatic and Adipocyte-derived Hormones

In addition to changes in gut peptides as mechanisms related to the significant weight loss and improvements in obesity-associated conditions, there may be a role for pancreatic and adipocyte-derived hormones.[111,112] For example, in a longitudinal study of short-term and long-term changes following RYGB, high-molecular-weight adiponectin increased 1 month after surgery, remained elevated for 12 months and were correlated with decreases in homeostatic model assessment-insulin resistance (HOMA-IR). Fasting glucagon and pancreatic polypeptide levels decreased after RYGB, and these reductions were independently associated with decreases in HOMA-IR.[112] Without a control group, however, it cannot be determined whether these changes are related uniquely to RYGB or occur in conjunction with the weight loss or negative energy balance that occurs after RYGB.

Overall, the extent to which the greater improvement in insulin sensitivity after RYGB and BPD-DS is related to greater weight loss, negative energy balance, altered release of gut and pancreatic hormones, or other factors remains a matter of speculation. The fact remains that weight loss per se is a central component in the improvements observed in all diseases related to obesity. We and others have demonstrated in controlled studies that peripheral glucose disposal; insulin resistance; reductions in leptin, resistin, and interleukin-6 levels; and increases in adiponectin levels are observed only after substantial weight loss has occurred and correlate with the magnitude of weight lost.[81,113,114] In addition, few of the studies that we reviewed documented improved liver histology changes with greater weight loss.[40,41]

The short- and long-term impact of all of these changes on glucose and lipid metabolism in the liver, adipose tissue, muscle, and pancreatic β-cell, and the interplay among metabolic processes occurring in these tissues, has not been comprehensively evaluated. These unresolved questions underscore the need to simultaneously evaluate and quantify the contribution of each of these tissues to the improvements observed after bariatric surgery.


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