Nonalcoholic Fatty Liver Disease and Bariatric Surgery

Sindu Stephen; Ancha Baranova; Zobair M Younossi

Disclosures

Expert Rev Gastroenterol Hepatol. 2012;6(2):163-171. 

In This Article

Pathogenesis of NAFLD

Hepatic fat accumulation is the initial event in the pathogenesis of NAFLD. The metabolic pathways leading to the development of hepatic steatosis include enhanced nonesterified fatty acid release from adipose tissue (lipolysis), increased de novo fatty acids (lipogenesis) and decreased β-oxidation.[15]

The secondary events of oxidative stress and increased inflammation are the key factors influencing the progression from simple steatosis to more advanced liver disease.[16] Hyperinsulinemia, mitochondrial stress, cytochrome P-450 enzymes, cytokines, iron overload and various toxins are some of the suspected sources of oxidative stress.[16,17] Currently, there are no clinically approved tests to predict whether a given patient with steatosis will in time develop steatohepatitis. Some researchers believe that steatosis and NASH are sequential steps within the same detrimental process that may be delayed in its progression for some time for various reasons. Indeed, some clearly adverse soluble factors (e.g., TGF-β and ferritin) are equally elevated in patients with simple steatosis and NASH, thus exerting a profibrotic pressure on histologically different, but susceptible, livers.[18]

Both insulin resistance and hepatic fibrogenesis are heavily influenced by physiological processes taking place in visceral adipose tissue (VAT).[19,20] This tissue compartment represents the largest endocrine organ of the human body that secretes soluble adipokines and cytokines into the bloodstream. Most of these molecules, in particular, TNF-α, IL-6, leptin, resistin and visfatin, promote insulin resistance and low-grade inflammation.[20] For example, adipocyte-derived IL-6 has been estimated to comprise 30% of the circulating IL-6, suggesting an endocrine action that may be exerted upon the liver.[21] The chronic inflammatory state has been implicated as a risk factor in the progression of NAFLD, as well as a contributor to several other conditions, including malignancy, obstructive sleep apnea, hypercoagulation and atherosclerosis.[22] Pertinent to NAFLD, increases of well-accepted biomarkers of liver function, especially alanine transaminase and γ-glutamyl transpeptidase, are associated with visceral fat mass.[23]

In addition to proinflammatory molecules, VAT produces adiponectin that prevents lipogenesis in the liver and protects from inflammation and fibrosis; however, the production of adiponectin decreases with an increase in BMI. Deficiency of adiponectin biosynthesis has been associated with NAFLD and NASH.[24] Another contributor to NAFLD is miRNAs differentially expressed in VAT.[25] The same is true for general gene-expression patterns in VAT: adipose from patients with NASH shows prominent deregulation of genes related to inflammation and the immune system, including adipose-specific functional networks, centered at TNF-α, JUN/JUNB and IFN-γ.[26]

Recently, a phenotype of 'metabolically benign' obesity has been described in adult populations. In these individuals, an increase in adipose mass is not paralleled by insulin resistance.[27] Importantly, some studies show the 'breaking point' between metabolically benign and 'metabolically malignant' obesity may be the hepatic accumulation of fat.[27] It has been shown that an increase in insulin resistance is accompanied by increase in both the degree of steatosis and levels of C-reactive protein, but not in BMI or waist circumference;[28] however, the role of other soluble factors reflecting low-grade chronic inflammation remains unknown. Currently, it is unknown what percentage of bariatric surgery patients, if any, could be classified as having metabolically benign obesity. Furthermore, it is unclear whether the benefits of bariatric surgery in metabolically benign obese patients are larger or smaller than in average morbidly obese patients. This question warrants further investigation.

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