Encyclopedia
Please note this is a comparison between Version 1 by Paulina Głuszyńska and Version 2 by Bruce Ren.
The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) has considerably increased over the last years. NAFLD is currently the most common cause of chronic liver disease in the developing world. The diagnosis of NAFLD/NASH is often incidental, as the early-stage of disease is frequently free of symptoms. Most patients recognized with NAFLD have severe obesity and other obesity-related disease such as type 2 diabetes mellitus (T2DM), insulin-resistance, dyslipidemia and hypertension. The only proven method for NAFLD improvement and resolution is weight loss. Bariatric surgery leads to significant and long-term weight loss as well as improvement of coexisting diseases.
- non-alcoholic fatty liver disease
- non-alcoholic steatohepatitis
- obesity
- bariatric surgery
- laparoscopic sleeve gastrectomy
- Roux-en-Y gastric bypass
1. Introduction
Unhealthy lifestyle and dietary habits have contributed to an alarming increase in obesity and obesity-related diseases worldwide. The epidemic of obesity has led to a significant increase in the prevalence of non-alcoholic fatty liver disease (NAFLD). The prevalence of NAFLD is 25–30% of the general population and 50–90% in patients with obesity [1][2][1,2]. A recent report estimates the constant increase in the prevalence of NAFLD by the year 2030 with significant rise in hepatocellular carcinoma (HCC) and liver-related deaths [3]. NAFLD is the initial, uncomplicated medical condition that may lead to end-stage liver disease from non-alcoholic simple steatosis and steatohepatitis (NASH) to fibrosis and liver cirrhosis with its clinical consequences such as: variceal bleeding, ascites, renal failure, encephalopathy and spontaneous bacterial peritonitis [4][5][4,5]. Data from the European Liver Transplant Registry (ELTR) and United Network for Organ Sharing (UNOS) show that NAFLD and NASH have been the most rapidly growing indication for liver transplant within the last 20 years. Additionally, NAFLD is presently the most frequent non-viral hepatitis-related indication for liver transplant among adults in the United States [6][7][6,7].
NAFLD is frequently recognized as the hepatic manifestation of metabolic syndrome (MS) and remains in close association with components of MS that include increased fasting plasma glucose level and type 2 diabetes mellitus (T2DM), increased waist circumference, hypertension and dyslipidemia [8][9][8,9]. Recent studies have shown that over 80% of patients undergoing bariatric surgery have been diagnosed with NAFLD or NASH [10][11][10,11].
Bariatric/metabolic surgery is an effective treatment for morbid obesity that provides sustained and considerable weight loss with the improvement of obesity-related diseases. Reduction in body weight induced by bariatric surgery leads to potential decrease in hepatic inflammation, fat accumulation and fibrosis [12].
2. Treatment Options of NAFLD
A considerable amount of research points out strong evidence between NASH and lifestyle modifications such as: weight loss, dietary changes and physical exercises. It has been proven that weight reduction by 5 to 10% in individuals with obesity can result with improvement in all features of NASH, including inflammation and fibrosis [13][46]. Dietary changes should include decrease in calorie intake, as well as changes in composition of a diet that includes reduction of carbohydrate intake (particularly simple carbohydrates, e.g., sweets, fruit juices, honey, fruits, flavored yoghurts), reduction of dietary fats with emphasis on saturated and trans fatty acids, increase in protein intake, ensuring supply of antioxidants, probiotics and prebiotics. Abstinence from alcohol is also recommended as a lifestyle intervention in NAFLD treatment [14][47]. However, it is very important to notice that implementing lifestyle modifications in patients with obesity can be problematic and usually does not bring the intended results. A study conducted by Dudekula et al. that aimed to find weight loss predictors in patients with obesity and NAFLD showed that 66% of research participants experienced weight reduction of less than 5% during the observation period. Weight loss between 5 to 10% was observed in 12.9% patients and reduction in body weight >10% was seen only in 6.9% of study participants [15][48]. Additionally, most individuals with obesity are more likely to regain weight in a short period of time [16][49]. The general idea of NAFLD treatment focuses on co-existing diseases such as obesity, dyslipidemia, insulin resistance and diabetes mellitus.
According to the European Association for the Study of the Liver (EASL) guidelines, pharmacological therapy should be implemented in patients with progressive NASH (bridging fibrosis and cirrhosis); early stage NASH with high risk for disease progression (increased ALT, presence of metabolic syndrome and diabetes mellitus, age >50 years) and active NASH with high necroinflammatory activities [17][50]. Pharmacological therapy options for NAFLD include: antidiabetic drugs, drugs modifying lipid profile, anti-obesity drugs, vitamin supplementation and novel therapeutic treatment that includes interference with inflammatory, fibrotic and apoptotic pathways. Among antidiabetics drugs pioglitazone, glucagon-like-peptide (GLP-1) analogues and liraglutide were found to be effective in NAFLD/NASH treatment. Pioglitazone was shown to significantly improve steatosis and inflammation, together with systemic and adipose- tissue resistance in one-year observation in patients with T2DM [18][51]. Research conducted by Bril et al. confirmed reduction of liver fibrosis and increase in adipose tissues insulin sensitivity. However, the effect was significantly greater in patients with type 2 diabetes than in patients with prediabetes [19][52]. Liraglutide is a long-acting GLP-1 agonist that improves key metabolic risk factors: weight, body mass index and glucose level. Besides its metabolic improvement, liraglutide was found to significantly improve liver steatosis in NAFLD patients by downregulating the expression of inflammatory mediators in the TNF-α signaling pathway [20][21][53,54]. Additionally, liraglutide affects the renin-angiotensin system (RAS), which is overactivated during NAFLD. Liraglutide was found to down regulate the ACE/Ang II/AT1R axis and antagonizes hepatocellular steatosis [22][55].
In the case of metformin, which is commonly used in prediabetes and diabetes treatment, no strong evidence for histological response was found in NAFLD patients [23][56]. Despite the fact that metformin has no specific influence on liver histology, it is recommended in NAFLD/NASH patients with T2DM due to its pleiotropic effect including reduction in body mass, and decrease in ALT activity and improvement of cardiovascular system [24][57]. Furthermore, a recent animal study conducted by Brandt et al. suggests that metformin has a protective effect on the development of NAFLD, which results from a protection against intestinal barrier impairment, e.g., loss of tight junction proteins. Metformin also alters intestinal microbiota composition in the proximal small intestine, which has a beneficial effect on steatosis development [25][58].
Vitamin supplementation has been also found to have its role in NAFLD treatment. Vitamins with antioxidant properties, such as Vitamin C and E decrease the oxidative stress that is seen in patients with NAFLD and NASH. Additionally, Vitamin E has anti-inflammatory and anti-apoptotic properties that can retard the fibrosis process and prevent from cirrhosis by modulating inflammatory response and cellular proliferation [26][59]. It should be mentioned that supplementation of Vitamin E is recommended for patients with NASH and stage 2 fibrosis proven in biopsy and without a family history of prostate cancer, as it was proven that high daily dose of Vitamin E (≥400 IU per day) is associated with progression of prostate cancer [27][60].
Data about usage of weight-loss medication in NAFLD are very scarce in the available literature. To date, only Orlistat was found to contribute to improvement in hepatic fat content, as well as the activity of ALT and AST during at least 24 weeks of therapy [28][61]. It is thought that Orlistat may have a potential beneficial effect on NAFLD as it stimulates weight loss, however it is not clear whether it has an independent effect on liver function. Other weight-loss medications such as naltrexone, bupropion and topiramate have no evidence of usefulness in NAFLD treatment [29][62].
The use of statins in NAFLD treatment is still controversial. Undoubtedly, statins decrease the level of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides, and hence limit the cardiovascular risk [30][63]. In the study conducted by Hyogo et al., patients were treated with 10 mg atorvastatin daily. Researchers observed significant reduction in AST, ALT and GGT concentrations as well as decrease in NAFLD Activity Score (NAS), which includes steatosis, hepatocyte ballooning and lobular inflammation [31][64]. The use of statins among patients with NAFLD should be implemented with co-existing dyslipidemia, as its protective effect on the cardiovascular system outweighs other adverse events and low efficacy on hepatic histopathology [14][47].
Among novel therapeutic perspectives, farnesoid X receptor (FXR) agonist has been investigated. Obeticholic acid (OCA or 6α-ethyl chenodeoxycholic acid, initially known as INT-747) is an FXR agonist registered for the treatment of primary biliary cholangitis due to its anticholestatic and hepatoprotective properties [32][65]. Data from recently performed clinical trials prove that OCA is effective in patients with biopsy-proven NASH or NAFLD [33][34][66,67]. The primary endpoint of FLINT study was histological improvement in NAFLD activity score of at least 2 points, which was achieved in 45% of patients receiving 25 mg OCA daily [33][66]. A study conducted by Mudaliar et al. showed that the administration of 25 or 50 mg OCA daily increases insulin sensitivity and reduces markers of hepatic inflammation and fibrosis in patient with NAFLD and T2DM [34][67]. Another farnesoid X receptor agonist, cilofexor (GS-9674) is under investigation as monotherapy or in combination with an acetyl-CoA carboxylase inhibitor, firsocostat (GS-0976). The combination of these two drugs showed improvement in liver steatosis and stiffness and serum markers of hepatic fibrosis [35][68]. Peroxisome proliferator-activated receptor (PPAR)-γ agonists such as rosiglitazone and pioglitazone have been under investigation for potential effects in NAFLD/NASH patients. The use of pioglitazone in patients with biopsy-proven NASH improves liver function and decreases liver fat content. Cusi et al. conducted a placebo-controlled RCT of 101 adults with NASH and T2DM. They documented that 58% of patients assigned to pioglitazone group (45 mg once daily) achieved the primary outcome (reduction in NAFLD activity score of at least 2 points without worsening of fibrosis) and 51% had resolution of NASH. Pioglitazone treatment was also associated with improvement in individual histological scores, including the fibrosis score, reducing hepatic triglyceride content from 19% to 7%, and improving adipose tissue, hepatic, and muscle insulin sensitivity [36][69]. A Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial showed that rosiglitazone improved steatosis and normalized transaminase levels in 47% of patients. However, no effect on other histologic lesions was documented [37][70].
Some experimental studies have focused on the specific inhibition of the fibrosis process in liver with the use of an inhibitory antibody to lysyl oxidase-2 (LOXL-2). LOXL-2 up-regulation was noticed in patients with NAFLD and T2DM and LOXL-2 hepatic and circulating levels correlate with histological fibrosis progression [38][71]. LOXL-2 inhibition paves the way for macrophage-mediated collagen degradation in liver fibrosis. However, in two phase 2b trails of patients with bonding fibrosis due to nonalcoholic steatohepatitis, simtuzumab (monoclonal LOXL-2 antibody) was found to be ineffective in decreasing hepatic collagen content [39][72]. Additionally, compounds interfering with apoptotic pathways have been investigated as a treatment option for NAFLD/NASH. An example is selonsertib, which is an inhibitor of the apoptosis signal-regulating kinase 1 (ASK1), and plays a significant role in hepatocyte inflammation, injury and fibrosis. In a phase 2 trial, selonsertib appeared to improve liver fibrosis in a substantial proportion of patients with NASH and stage 2 or 3 fibrosis, suggesting its potential use in NAFLD pharmacological therapy [40][73]. However, results from randomized phase III STELLAR trials did not show evidence that selonsertib reduces fibrosis in patients with NASH and advanced liver scarring [41][74].
3. Bariatric Surgery and NAFLD
Bariatric surgery aims not only to achieve considerable, long-term weight loss but also to improve the course of obesity-related diseases such as T2DM, hypertension, dyslipidemia, obstructive sleep apnea. It also reduces the risk of cardiovascular diseases such as myocardial infarction and ischemic stroke and decreases overall mortality [42][43][44][75,76,77]. A meta-analysis conducted by Sutanto et al. showed significant reduction in the incidence of major adverse cardiovascular events in bariatric surgery group as compared to the no-surgery group (OR = 0.49; 95% CI 0.40–0.60; p < 0.00001; I2 = 93%) [45][78]. Among recently available surgical methods, Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) are the most commonly performed worldwide. A study conducted by Mummadi et al. summarized 15 studies with 766 paired liver biopsies. Their investigation showed the pooled proportion of patients with improvement or resolution in steatosis was 91.6% (95% confidence interval (CI), 82.4–97.6%), in steatohepatitis was 81.3% (95% CI, 61.9–94.9%), in fibrosis was 65.5% (95% CI, 38.2–88.1%), and for complete resolution of NASH was 69.5% (95% CI, 42.4–90.8%) after bariatric surgery [46][79]. The Swedish Obese Subjects (SOS) study showed reduction in both ALT and AST values after bariatric surgery in both short and long-term observation (2 and 10-year follow-up) [47][80].
NAFLD is closely associated with obesity, T2DM and other features of metabolic syndrome. All mechanisms involved in improving obesity and T2DM that appear after bariatric surgery seem to have a crucial role in amelioration or resolution of NAFLD. Weight reduction due to bariatric surgery causes inflammatory changes in patients with obesity. Klein et al. showed that gastric bypass procedure decreases the hepatic expression of factors involved in the progression of liver inflammation (macrophage chemoattractant protein 1 (MCP-1), and interleukin (IL-8)) and fibrogenesis (transforming growth factor-β1 (TGF-β1), tissue inhibitor of metalloproteinase 1 (TIMP-1), α-smooth muscle actin (α-SMA), and collagen-α1(I)) [48][81]. Cazzo et al. showed a significant decrease in mean NAFLD fibrosis score after RYGB and resolution rate of 55% of severe fibrosis in 12-month observation [49][82]. Moreover, RYGB contributes to significant reduction in NAFLD activity score, steatosis, inflammation and liver ballooning during 1-year observation [50][51][83,84].
LSG is also considered to improve the course of NAFLD. Nobili et al. showed reduced activation of local cellular compartments (hepatic progenitor cells, hepatic stellated cells, macrophages) induced by LSG, which led to the improvement in NAFLD Activity Score and liver fibrosis [52][85]. A study conducted by Cabré et al. proved that the histology and liver function of patients with morbid obesity significantly improved after LSG due to mechanisms involved in the reduction of oxidative stress and inflammation. They observed significant reduction in the hepatic immunochemical expression of oxidation, inflammation and fibrosis markers such as: PON-1, 4-hydroxy-2-nonenal, CD68, chemokine ligand 2 (CCL2), C-C chemokine receptor type 2 (CCR2), TNF-α, and galectin-3 between baseline liver tissue and 12 months after LSG [53][86]. Weight loss induced by LSG leads to the improvement in liver histology in terms of steatosis, liver fibrosis, lobular inflammation and hepatocyte ballooning. In a study conducted by Salman et al., among 81 patients undergoing LSG, 9 (11.1%) showed no steatosis at the end of 18-month follow-up, 25 (30.9%) showed no hepatocyte ballooning, 37 (45.7%) showed no lobular inflammation, and 33 (40.7%) showed complete absence of fibrosis. The above-mentioned study also showed significant improvement in postoperative liver function tests (AST, ALT, GGTP). An 18-month observation also revealed an increase in adiponectin levels and a reduction in serum levels of leptin and resistin, when compared to presurgical values. The above-mentioned data prove that both LSG and RYGB are significant surgical methods for NAFLD/NASH treatment [54][87].
As presented above, bariatric surgery provides proven NAFLD amelioration; however, the remaining question is whether RYGB or LSG is more effective. A systematic review and meta-analysis performed by Baldwin et al. compared RYGB and LSG using 4 separate criteria: AST and ALT concentration, NAFLD activity score and NAFLD fibrosis score. Patients undergoing both procedures showed significant reduction in AST and ALT values. Head-to-head comparison of AST mean differences trended toward LSG, but it was statistically non-significant. This study failed to show superiority between RYGB and LSG in ameliorating NAFLD [55][88]. Cherla et al. also proved the normalization of the liver function test by the end of the first postoperative year; however, they did not find significant differences between the SG and RYGB groups [56][89]. A meta-analysis performed by Silva et al. showed that RYGB patients achieve significant reduction of steatohepatitis and fibrosis, while patients undergoing LSG presented significant reduction only of steatohepatitis. According to their study, the NAFLD Activity Score significantly improved after both procedures and no differences were found between LSG and RYGB regarding histopathological changes [57][90]. A study conducted by Pedersen et al. showed that NAS reduced significantly in both RYGB and LSG patients 12-months after the surgery. However, RYGB patients had significantly more reduced (p = 0.007) liver steatosis (−0.91 (95% CI −1.47–−1.2) than SG patients (−0.33 (95% CI −0.54–−0.13) and greater improvement in the plasma lipid profile [50][83]. Luo at el. investigated liver volume and fat density in MRI in patients undergoing bariatric surgery. Their study showed that RYGB patients achieved higher weight loss and higher BMI loss when compared to the LSG group. However, the percentage decrease in liver volume and MRI-PDFF did not differ significantly between groups [58][91].
Despite the significant role of bariatric surgery in the treatment of NAFLD, there are some patients that will develop new or worsened features of NAFLD after bariatric procedure. The meta-analysis performed by Lee et al. showed that 12% of patients experienced development or worsening of NAFLD (95% CI, 5–20%) [59][92]. A 5-year prospective study performed by Mathurin et al. showed that 19.8% of patients experienced fibrosis progression 5 years after bariatric surgery for unknown reason [60][93]. Aggravation of NAFLD after bariatric procedure should be kept in mind when qualifying patients for bariatric surgery.
